WO2025083211A1 - Use of factor h for the treatment of dementia - Google Patents

Abstract

The inventors hypothesized that inhibition of complement activation could reduce the inflammatory period observed even before clinical signs of Alzheimer's disease and thus slow down the onset and progression of AD. In order to validate the hypothesis, the inventors injected Factor H (FH: the main inhibitor of complement activation) into the brain of APP/PS1 AD- mice model at early or late stage of this pathology. The results showed effects of FH brain injection on the AD-onset as well as progression by reducing pro-inflammatory IL6, TNF-α, Il1β, MAC and Aβ levels associated with an increase of VGLUT1 and Psd95 neurotransmitters levels in hippocampal region leading to improvement of cognitive functions even at late stage of the pathology. The results thus prompt the inventors to consider that FH would be suitable for the treatment of dementia, and more particularly for the curative treatment of dementia.

Description

USE OF FACTOR H FOR THE TREATMENT OF DEMENTIA FIELD OF THE INVENTION: The present invention is in the field of medicine, in particular neurology. BACKGROUND OF THE INVENTION: Alzheimer disease (AD) is an increasing prevalence pathology with the aging of the world. The number of affected populations is underestimated, due to the late diagnosis which is currently based on scoring clinical symptoms including loss of cognitive functions, such as trouble remembering recent events and eventually total memory loss that interfere with the individuals’ ability to perform daily tasks. Most neurodegenerations such as AD present common processes, namely an angiopathy, or vascular dementia, associated with inflammation, and ultimately leading to neuronal death resulting in cognitive impairments. The two major hallmarks of AD are accumulation of extracellular deposits of amyloid beta (Aβ) into plaques and of intracellular abnormally or hyperphosphorylated tau protein (neurofibrillary tangles) in brain regions related to memory¹. Currently, there is no real treatment for AD. Previous treatments do not treat the cause but the consequences of the disease. Therapies include comprehensive medical and psychosocial support and caregiving². Hence, non-pharmacologic measures and behavioral treatments are the first lines of cure. For several decades, treatment strategies targeting Aβ protein have been developed around the immunization with Aβ itself leads to reduction of pathology in Alzheimer models such as improvement of cognitive functions³. The recent clinical trials of Lecanemab (Leqembi) or Donanemab in AD is proof that reducing brain Aβ has a clear benefit on cognitive functions 27%⁴ and 35%⁵ respectively, consistent with the amyloid hypothesis⁶. However, these treatments is not effective for all patients (mild cognitive impairment or at an early stage of the disease) and carries some risks (the main adverse events identified was edema in the brain)⁴. However, even before presenting clinical signs, the pathology settles in the brain 15 to 20 years earlier. This stage, called pre-symptomatic, presents a cerebral neuroinflammation that will be out of control over time and a factor more favorable to the installation of the pathology leading to the loss of neurons associated with cognitive functions impairments. In this preclinical phase, individuals are often clinically asymptomatic but show evidence of AD neuropathology⁷. Several studies have noted that the pathological changes which characterize AD could all result from complement activation in neuritic Aß plaques, since the complement system activates various cells types with release of cytokines and alters cellular functions and induces damages cells^8–10. The Aβ plaques are associated with inflammation such as activated complement protein deposits, both events could reflect an aggressive level of activity which could be an important contributor to AD pathogenesis^11,12. Among the genetic risks to develop AD are polymorphism for complement proteins: C1s (rs7311672), which is an inducer of complement activation and complement factor H (FH -Y402H), the major inhibitor of complement cascade¹³. In addition, it has been shown that overactivation of this pathway is an aggravating factor in AD^11,12. The complement system is an important humoral immune surveillance mechanism against infections or tissue lesions. It is a collection of blood and cell surface proteins that are grouped together to be activated. Activated complement acts as a powerful amplifier of the innate and acquired immunity by increasing antibody responses and immunologic memory, by lysing foreign cells and clearing immune complexes and apoptotic cells. The major event leading to the activation of the 3 complement pathways, classical, lectin or alternative (the last one serves as an amplification loop), is the cleavage of C3 by a C3 convertase complex into a C3a anaphylactic protein, and a C3b opsin protein involved in phagocytosis and in the C3/C5 convertase complex formation. Ordinarily the C3b is quickly inactivated: C3b binds to inhibitory proteins and sialic acids present on the surface of the body's own cells, and the process is aborted. On the other hand, once C3 cleavage comes from injury, it also triggers, through the C5 convertase complex, the formation of an anaphylactic/chemotactic C5a product and of a membranolytic complex (C5b-9 or MAC). In tissue lesions, C3a/C5a , C3b and MAC are markers of activated complement and are mediators of local inflammatory processes. Activation of the complement system must be tightly regulated, since it has the potential to be extremely damaging to host tissues. Thus, the main soluble inhibitor of complement is the complement factor H (FH), a 155kda Sushi protein, that acts in body fluids as well as on cell surfaces by preventing the formation and accelerating the decay of the C3/C5 convertases and by assisting the degradation of C3b, thereby breaking the complement positive C3 convertase complex feedback loop. FH could also regulate some complement-independent processes such as apoptosis, angiogenesis or oxidative stress which are involved in the development of AD^10-11. In the brain of AD patients, levels of C3, the major compound of complement activation, are up regulated and in AD-mice models blocking this protein rescues synapse loss which improves neurophysiological and behavioral measurements^7-8. A large body of previous studies of C5aR signaling indicate that the anaphylactic C5a produces a proinflammatory microenvironment leading to generation of cytokines of many of which are known to be implicated in AD progression⁹. Altogether these data clearly show a role of complement activation in the progression of AD. SUMMARY OF THE INVENTION: The present invention is defined by the claims. In particular, the present invention relates to the use of factor H for the treatment of dementia. DETAILED DESCRIPTION OF THE INVENTION: The complement cascade is a part of the innate immune system in order to fight infections as well as tissue damage or age related. The activation of this system creates an inflammatory microenvironment that enhances phagocytosis/inflammation and/or cell death. An exacerbated complement inflammatory activity has been described as a poor prognosis for maintaining blood barriers structure and functions which could lead to neurodegenerative disease such as Alzheimer disease (AD). In AD preclinical phase, individuals are often clinically asymptomatic despite evidences of AD neuropathology coupled with an exacerbated inflammation. By taking into account the involvement of complement in the risk of developing AD or even in the progression of this disease, the inventors hypothesized that inhibition of complement activation could reduce this inflammatory period observed even before clinical signs and thus slow down the onset and progression of AD. In order to validate the hypothesis, the inventors injected Factor H (FH: the main inhibitor of complement activation) into the brain of APP/PS1 AD- mice model at early or late stage of this pathology. The results showed effects of FH brain injection on the AD-onset as well as progression by reducing pro-inflammatory IL6, TNF-α, Il1β, MAC and Aβ levels associated with an increase of VGLUT1 and Psd95 neurotransmitters levels in hippocampal region leading to improvement of cognitive functions even at late stage of the pathology. The results thus prompt the inventors to consider that FH would be suitable for the treatment of AD, and more particularly for the curative treatment of AD. Main definitions: As used herein, the term “dementia” denotes a decline in cognitive function causing impairment that interferes with independence in everyday activities (American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders 5th ed. American Psychiatric Association; 2013). As used herein, the term “vascular cognitive impairment and dementia” refers to cognitive impairment or dementia that results from a cerebral small disease. As used herein, the term “cerebral small vessel disease” or “CSVD” has its general meaning in the art and refers to a group of several diseases affecting the small arteries, arterioles, venules, and capillaries of the brain, and refers to several pathological processes and etiologies (Li Q, Yang Y, Reis C, Tao T, Li W, Li X, Zhang JH. Cerebral Small Vessel Disease. Cell Transplant. 2018 Dec;27(12):1711-1722. doi: 10.1177/0963689718795148). Neuroimaging features of CSVD include recent small subcortical infarcts, lacunes, white matter hyperintensities, perivascular spaces, microbleeds, and brain atrophy. The main clinical manifestations of CSVD include stroke, cognitive decline, dementia, psychiatric disorders, abnormal gait, and urinary incontinence. Vascular cognitive impairment and dementia are among the most common causes of dementia after Alzheimer disease (AD) (Rizzi L, Rosset I, Roriz-Cruz M. Global epidemiology of dementia: Alzheimer’s and vascular types. Biomed Res Int 2014;2014(908915)). As used herein, the term “Alzheimer’s disease” or “AD” has its general meaning in the art and refers to a neurodegenerative disorder marked by cognitive and behavioural impairment that significantly interferes with social and occupational functioning. It is a disease with a long preclinical period and progressive course. The two major hallmarks of AD are accumulation of extracellular deposits of amyloid beta (Aβ) into plaques and of intracellular abnormally or hyperphosphorylated tau protein (neurofibrillary tangles) in brain regions related to memory¹. Individuals with AD progress through pre-symptomatic to symptomatic stages, often termed preclinical prodromal (mild cognitive impairment [MCI]), mild, moderate, and severe dementia. There are several different tools memory care professionals use to determine an individual’s dementia progression. The most commonly used scales are the Global Deterioration Scale (GDS), the Clinical Dementia Rating (CDR) and the Functional Assessment Staging Test (FAST). For instance, according to the Global Deterioration Scale, the course of ADs is generally described in 7 stages, with a progressive pattern of cognitive and functional impairment wherein stages 1-3 are the pre-dementia stages, and stages 4-7 are the dementia stages (Table A). Table A: The seven clinical stages of Alzheimer’s disease (Global Deterioration Scale) (Reisberg B, Ferris S, De Leon M, Crook T. The Global Deterioration Scale for assessment of primary degenerative dementia. Am J Psychiatry.1982 Sep;139(9):1136–9.) Symptoms and characteristics Stage Persons appear cognitively normal, but pathological changes are happening in the 1 brain. Stage Prodromal stage: mild memory loss, but generally this is indistinguishable from 2 normal forgetfulness. Stage Progression into mild cognitive impairment (MCI). Individuals may get lost or have 3 difficulty in finding correct wording. Stage Moderate dementia; poor short-term memory. Individuals forget some of their 4 personal history. Stage Cognition continues to decline and at this point individuals need help in their daily 5 lives. They suffer from confusion and forget many personal details. Stage Severe dementia. Requiring constant supervision and care. Patients fail to recognize 6 many of their family and friends and have personality changes. Stage Individuals are nearing death. They show motor symptoms, have difficulty 7 communicating, are incontinent and require assistance in feeding. As used herein, the term “cognitive function” is a broad term that refers to mental processes involved in the acquisition of knowledge, manipulation of information, and reasoning. Cognitive functions include the domains of perception, memory, learning, attention, decision making, and language abilities. Typically, the Alzheimer’s Disease Assessment Scale– Cognitive Subscale (ADAS-Cog) (Rosen WG, Mohs RC, Davis KL (1984) A new rating Scale for Alzheimer’s disease. Am J Psychiatry 141, 1356–1364) is considered as the gold standard for assessing the cognitive function in AD. As used herein, the term "treatment" or "treat" refer to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of patient at risk of contracting the disease or suspected to have contracted the disease as well as patients who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse. The treatment may be administered to a patient having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a patient beyond that expected in the absence of such treatment. By "therapeutic regimen" is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy. A therapeutic regimen may include an induction regimen and a maintenance regimen. The phrase "induction regimen" or "induction period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease. The general goal of an induction regimen is to provide a high level of drug to a patient during the initial period of a treatment regimen. An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both. The phrase "maintenance regimen" or "maintenance period" refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a patient during treatment of an illness, e.g., to keep the patient in remission for long periods of time (months or years). A maintenance regimen may employ continuous therapy (e.g., administering a drug at regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]). As used herein, the term “curative treatment” also known as “therapeutic treatment”, is focused on treating existing diseases, conditions, or health problems after they have already developed. The goal of curative treatment is to alleviate symptoms, eliminate the cause of the problem, and restore the patient to a healthier state. Curative treatment is reactive, as it addresses health issues that have already manifested and are causing problems for the patient. The term is thus distinguishable from the term “preventive treatment”. Indeed, the term “preventive treatment” also known as “prophylactic treatment”, aims to prevent the development of diseases, conditions, or health problems before they occur. The goal of preventive treatment is to reduce the risk factors associated with a particular health issue and promote overall well-being. Preventive treatment is proactive, as it focuses on minimizing the likelihood of health problems arising in the first place. Thus, curative treatment is administered after a health issue has developed, while preventive treatment is administered before any health problems arise. Curative treatment targets existing diseases or conditions and aims to provide relief and cure. Preventive treatment focuses on reducing the risk of developing diseases or conditions. Curative treatment addresses the symptoms and root causes of a specific health problem. Preventive treatment emphasizes lifestyle changes and interventions to minimize risk factors. The goal of curative treatment is to restore the patient's health and eliminate the disease or condition. The goal of preventive treatment is to maintain good health and avoid the onset of diseases. As used herein, the terms “polypeptide”, “peptide”, and “protein” are used interchangeably herein to refer to polymers of amino acids of any length. The terms also encompass an amino acid polymer that has been modified; for example, disulfide bond formation, glycosylation, lipidation, phosphorylation, or conjugation with a labeling component. Polypeptides when discussed in the context of gene therapy refer to the respective intact polypeptide, or any fragment or genetically engineered derivative thereof, which retains the desired biochemical function of the intact protein. As used herein, the term “polynucleotide” refers to a polymeric form of nucleotides of any length, including deoxyribonucleotides or ribonucleotides, or analogs thereof. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs, and may be interrupted by non-nucleotide components. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. The term polynucleotide, as used herein, refers interchangeably to double- and single-stranded molecules. Unless otherwise specified or required, any embodiment of the invention described herein that is a polynucleotide encompasses both the double-stranded form and each of two complementary single-stranded forms known or predicted to make up the double-stranded form. As used herein, the term "encoding" refers to the inherent property of specific sequences of nucleotides in a polynucleotide, such as, for example, a gene, a cDNA, or an mRNA, to serve as templates for synthesis of other polymers and macromolecules in biological processes having either a defined sequence of nucleotides (e.g., rRNA, tRNA and mRNA) or a defined sequence of amino acids and the biological properties resulting therefrom. Thus, a gene, cDNA, or RNA, encodes a protein if transcription and translation of mRNA corresponding to that gene produces the protein in a cell or other biological system. Both the coding strand, the nucleotide sequence of which is identical to the mRNA sequence and is usually provided in sequence listings, and the non-coding strand, used as the template for transcription of a gene or cDNA, can be referred to as encoding the protein or other product of that gene or cDNA. Unless otherwise specified, a "nucleotide sequence encoding an amino acid sequence" includes all nucleotide sequences that are degenerate versions of each other and that encode the same amino acid sequence. The phrase “nucleotide sequence that encodes a protein or a RNA” may also include introns to the extent that the nucleotide sequence encoding the protein may in some version contain an intron(s). As used herein, the “percent identity” between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions/total number of positions x 100), taking into account the number of gaps, and the length of each gap, which need to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm, as described below. The percent identity between two amino acid sequences can be determined using the Needleman and Wunsch algorithm (Needleman, Saul B. & Wunsch, Christian D. (1970). "A general method applicable to the search for similarities in the amino acid sequence of two proteins". Journal of Molecular Biology.48 (3): 443–53.). The percent identity between two nucleotide or amino acid sequences may also be determined using for example algorithms such as EMBOSS Needle (pair wise alignment; available at www.ebi.ac.uk). For example, EMBOSS Needle may be used with a BLOSUM62 matrix, a “gap open penalty” of 10, a “gap extend penalty” of 0.5, a false “end gap penalty”, an “end gap open penalty” of 10 and an “end gap extend penalty” of 0.5. In general, the “percent identity” is a function of the number of matching positions divided by the number of positions compared and multiplied by 100. For instance, if 6 out of 10 sequence positions are identical between the two compared sequences after alignment, then the identity is 60%. The % identity is typically determined over the whole length of the query sequence on which the analysis is performed. Two molecules having the same primary amino acid sequence or polynucleotide sequence are identical irrespective of any chemical and/or biological modification. According to the invention a first amino acid sequence having at least 80% of identity with a second amino acid sequence means that the first sequence has 80; 81; 82; 83; 84; 85; 86; 87; 88; 89; 90; 91; 92; 93; 94; 95; 96; 97; 98; 99 or 100% of identity with the second amino acid sequence. As used herein, the term “Factor H” or “FH” has its general meaning in the art and refers to a glycoprotein involved in regulation of the alternative complement pathway. In particular FH regulates the alternative complement pathway by controlling the amplification loop of the alternative pathway. FH binds to C3b, which results in accelerated dissociation of the C3 (C3bBb) or C5 (C3bBbC3b) alternative convertase, which thus becomes inactive. In addition, the FH bound to C3b acts as co-factor for Factor I (FI), enabling it to cleave C3b into C3bi, a molecule unable to bind to Factor B (FB) to form C3bBb. In terms of structure, FH has repetitive sequences of approximately 60 amino acids called “SCR domains” (short consensus repeat) or “sushi domains”. SCR 1-3 domains represents the minimal unit capable of cofactor activity (PubMed:18252712). Sushi 1-3 domain represents the minimal unit capable of cofactor activity (Hocking, Henry G., et al. "Structure of the N-terminal region of complement factor H and conformational implications of disease-linked sequence variations." Journal of Biological Chemistry 283.14 (2008): 9475-9487). An exemplary amino acid sequence of FH is shown as SEQ ID NO:1. Typically, sushi 1 domain ranges from the amino acid residue at position 19 to the amino acid residue at position 82 in SEQ ID NO:1, sushi 2 domain ranges from the amino acid residue at position 83 to the amino acid residue at position 143 in SEQ ID NO:1 and sushi 3 domain ranges from the amino acid residue at position 144 to the amino acid residue at position 207 in SEQ ID NO:1. SEQ ID NO:1 >sp|P08603|CFAH_HUMAN Complement factor H OS=Homo sapiens OX=9606 GN=CFH PE=1 SV=4 MRLLAKIICLMLWAICVAEDCNELPPRRNTEILTGSWSDQTYPEGTQAIYKCRPGYRSLG NVIMVCRKGEWVALNPLRKCQKRPCGHPGDTPFGTFTLTGGNVFEYGVKAVYTCNEGYQL LGEINYRECDTDGWTNDIPICEVVKCLPVTAPENGKIVSSAMEPDREYHFGQAVRFVCNS GYKIEGDEEMHCSDDGFWSKEKPKCVEISCKSPDVINGSPISQKIIYKENERFQYKCNMG YEYSERGDAVCTESGWRPLPSCEEKSCDNPYIPNGDYSPLRIKHRTGDEITYQCRNGFYP ATRGNTAKCTSTGWIPAPRCTLKPCDYPDIKHGGLYHENMRRPYFPVAVGKYYSYYCDEH FETPSGSYWDHIHCTQDGWSPAVPCLRKCYFPYLENGYNQNYGRKFVQGKSIDVACHPGY ALPKAQTTVTCMENGWSPTPRCIRVKTCSKSSIDIENGFISESQYTYALKEKAKYQCKLG YVTADGETSGSITCGKDGWSAQPTCIKSCDIPVFMNARTKNDFTWFKLNDTLDYECHDGY ESNTGSTTGSIVCGYNGWSDLPICYERECELPKIDVHLVPDRKKDQYKVGEVLKFSCKPG FTIVGPNSVQCYHFGLSPDLPICKEQVQSCGPPPELLNGNVKEKTKEEYGHSEVVEYYCN PRFLMKGPNKIQCVDGEWTTLPVCIVEESTCGDIPELEHGWAQLSSPPYYYGDSVEFNCS ESFTMIGHRSITCIHGVWTQLPQCVAIDKLKKCKSSNLIILEEHLKNKKEFDHNSNIRYR CRGKEGWIHTVCINGRWDPEVNCSMAQIQLCPPPPQIPNSHNMTTTLNYRDGEKVSVLCQ ENYLIQEGEEITCKDGRWQSIPLCVEKIPCSQPPQIEHGTINSSRSSQESYAHGTKLSYT CEGGFRISEENETTCYMGKWSSPPQCEGLPCKSPPEISHGVVAHMSDSYQYGEEVTYKCF EGFGIDGPAIAKCLGEKWSHPPSCIKTDCLSLPSFENAIPMGEKKDVYKAGEQVTYTCAT YYKMDGASNVTCINSRWTGRPTCRDTSCVNPPTVQNAYIVSRQMSKYPSGERVRYQCRSP YEMFGDEEVMCLNGNWTEPPQCKDSTGKCGPPPPIDNGDITSFPLSVYAPASSVEYQCQN LYQLEGNKRITCRNGQWSEPPKCLHPCVISREIMENYNIALRWTAKQKLYSRTGESVEFV CKRGYRLSSRSHTLRTTCWDGKLEYPTCAKR As used herein, the term “pharmaceutical composition” refers to a composition described herein, or pharmaceutically acceptable salts thereof, with other agents such as carriers and/or excipients. The pharmaceutical compositions as provided herewith typically include a pharmaceutically acceptable carrier. As used herein, the term “pharmaceutically acceptable carrier” includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's Pharmaceutical-Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutical compositions and known techniques for the preparation thereof. As used herein, the term "therapeutically effective amount" is meant a sufficient amount of the active ingredient for treating or reducing the symptoms at reasonable benefit/risk ratio applicable to any medical treatment. It will be understood that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination with the active ingredients; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than those required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. However, the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day. Typically, the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the active ingredient for the symptomatic adjustment of the dosage to the subject to be treated. A medicament typically contains from about 0.01 mg to about 500 mg of the active ingredient, typically from 1 mg to about 100 mg of the active ingredient. An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.

Methods of the present invention: The first object of the present invention relates to a method of treating dementia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a factor H (FH) polypeptide or a polynucleotide encoding thereof. More particularly, the method of the present invention is suitable for the curative of dementia. In particular, the method of the present invention is suitable for the treatment of vascular cognitive impairment and dementia (VCID). More particularly, the method of the present invention is suitable for the curative treatment of VCID. In particular, the method of the present invention is suitable for the treatment of Alzheimer’s disease. More particularly, the method of the present invention is suitable for the curative treatment of AD. Thus, in some embodiments, the patient to be treated is at a symptomatic stage of the disease and typically is at a dementia stage. Typically, the patient is at stage 4 or over according to the Global Deterioration Scale (GDS). In some embodiments, the method of the present invention is particularly suitable for improving the cognitive function. In some embodiments, the method of the present invention is particularly suitable for improving memory function. In some embodiments, the FH polypeptide of the present invention comprises or consists of an amino acid sequence having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue at position 19 to the amino acid residue at position 207 in SEQ ID NO:1. In some embodiments, the FH polypeptide comprises or consists of an amino acid sequence having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue at position 19 to the amino acid residue at position 1231 in SEQ ID NO:1. According to the invention, the polypeptides of the invention may be produced by conventional automated peptide synthesis methods or by recombinant expression. General principles for designing and making proteins are well known to those of skill in the art. The polypeptides of the invention may be synthesized in solution or on a solid support in accordance with conventional techniques. Various automatic synthesizers are commercially available and can be used in accordance with known protocols as described in Stewart and Young; Tam et al., 1983; Merrifield, 1986 and Barany and Merrifield, Gross and Meienhofer, 1979. The polypeptides of the invention may also be synthesized by solid-phase technology employing an exemplary peptide synthesizer such as a Model 433A from Applied Biosystems Inc. The purity of any given protein; generated through automated peptide synthesis or through recombinant methods may be determined using reverse phase HPLC analysis. Chemical authenticity of each peptide may be established by any method well known to those of skill in the art. As an alternative to automated peptide synthesis, recombinant DNA technology may be employed wherein a nucleotide sequence which encodes a protein of choice is inserted into an expression vector, transformed or transfected into an appropriate host cell and cultivated under conditions suitable for expression as described herein below. Recombinant methods are especially preferred for producing longer polypeptides. A variety of expression vector/host systems may be utilized to contain and express the peptide or protein coding sequence. These include but are not limited to microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid or cosmid DNA expression vectors; yeast transformed with yeast expression vectors (Giga-Hama et al., 1999); insect cell systems infected with virus expression vectors (e.g., baculovirus, see Ghosh et al., 2002); plant cell systems transfected with virus expression vectors (e.g., cauliflower mosaic virus, CaMV; tobacco mosaic virus, TMV) or transformed with bacterial expression vectors (e.g., Ti or pBR322 plasmid; see e.g., Babe et al., 2000); or animal cell systems. Those of skill in the art are aware of various techniques for optimizing mammalian expression of proteins, see e.g., Kaufman, 2000; Colosimo et al., 2000. Mammalian cells that are useful in recombinant protein productions include but are not limited to VERO cells, HeLa cells, Chinese hamster ovary (CHO) cell lines, COS cells (such as COS-7), W138, BHK, HepG2, 3T3, RIN, MDCK, A549, PC12, K562 and 293 cells. Exemplary protocols for the recombinant expression of the peptide substrates or fusion polypeptides in bacteria, yeast and other invertebrates are known to those of skill in the art and a briefly described herein below. Mammalian host systems for the expression of recombinant proteins also are well known to those of skill in the art. Host cell strains may be chosen for a particular ability to process the expressed protein or produce certain post-translation modifications that will be useful in providing protein activity. Such modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation and acylation. Post- translational processing which cleaves a "prepro" form of the protein may also be important for correct insertion, folding and/or function. Different host cells such as CHO, HeLa, MDCK, 293, WI38, and the like have specific cellular machinery and characteristic mechanisms for such post-translational activities and may be chosen to ensure the correct modification and processing of the introduced, foreign protein. In some embodiments, the polynucleotide that encodes the FH polypeptide of the present invention is a messenger RNA (mRNA). In some embodiments, the polynucleotide is inserted in a vector, such as a plasmid, cosmid, episome, artificial chromosome, phage or a viral vector. Typically, the vector is a viral vector which is an adeno-associated virus (AAV), a retrovirus, bovine papilloma virus, an adenovirus vector, a lentiviral vector, a vaccinia virus, a polyoma virus, or an infective virus. Typically, the vector of the present invention include "control sequences", which refers collectively to promoter sequences, polyadenylation signals, transcription termination sequences, upstream regulatory domains, origins of replication, internal ribosome entry sites ("IRES"), enhancers, and the like, which collectively provide for the replication, transcription and translation of a coding sequence in a recipient cell. Not all of these control sequences need always be present so long as the selected coding sequence is capable of being replicated, transcribed and translated in an appropriate host cell. Another nucleic acid sequence, is a "promoter" sequence, which is used herein in its ordinary sense to refer to a nucleotide region comprising a DNA regulatory sequence, wherein the regulatory sequence is derived from a gene which is capable of binding RNA polymerase and initiating transcription of a downstream (3'-direction) coding sequence. Transcription promoters can include "inducible promoters" (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), "repressible promoters" (where expression of a polynucleotide sequence operably linked to the promoter is induced by an analyte, cofactor, regulatory protein, etc.), and "constitutive promoters”. In some embodiments, the polypeptide or polynucleotide of the present invention can be conjugated to at least one other molecule. Typically, said molecule is selected from the group consisting of polynucleotides, polypeptides, lipids, lectins, carbohydrates, vitamins, cofactors, and drugs. Typically, the active ingredient of the present invention (i.e. the polypeptide or polynucleotide) is combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form pharmaceutical compositions. In some embodiments, the polypeptide or polynucleotide of the present invention is formulated with lipidoids. The synthesis of lipidoids has been extensively described (see Mahon et al., Bioconjug Chem.201021:1448-1454; Schroeder et al., J Intern Med.2010267:9-21; Akinc et al., Nat Biotechnol. 200826:561-569; Love et al., Proc Natl Acad Sci USA. 2010107:1864- 1869; Siegwart et al., Proc Natl Acad Sci US A.2011108:12996-3001). While these lipidoids have been used to effectively deliver double stranded small interfering RNA molecules in rodents and non-human primates (see Akinc et al., Nat Biotechnol. 200826:561-569; Frank- Kamenetsky et al., Proc Natl Acad Sci USA.2008105:11915-11920; Akinc et al., Mol Ther. 200917:872-879; Love et al., Proc Natl Acad Sci USA.2010107:1864-1869; Leuschner et al., Nat Biotechnol.201129:1005-1010), the present disclosure describes their formulation and use in delivering polynucleotides. In some embodiments, the polypeptide or polynucleotide of the present invention is formulated using one or more lipid-based structures that include but are not limited to liposomes, lipoplexes, or lipid nanoparticles (Paunovska, Kalina, David Loughrey, and James E. Dahlman. "Drug delivery systems for RNA therapeutics." Nature Reviews Genetics (2022): 1-16). Liposomes are artificially-prepared vesicles which can primarily be composed of a lipid bilayer and can be used as a delivery vehicle for the administration of pharmaceutical formulations. Liposomes can be of different sizes such as, but not limited to, a multilamellar vesicle (MLV) which can be hundreds of nanometers in diameter and can contain a series of concentric bilayers separated by narrow aqueous compartments, a small unicellular vesicle (SUV) which can be smaller than 50 nm in diameter, and a large unilamellar vesicle (LUV) which can be between 50 and 500 nm in diameter. Liposome design can include, but is not limited to, opsonins or ligands in order to improve the attachment of liposomes to unhealthy tissue or to activate events such as, but not limited to, endocytosis. Liposomes can contain a low or a high pH in order to improve the delivery of the pharmaceutical formulations. As a non-limiting example, liposomes such as synthetic membrane vesicles are prepared by the methods, apparatus and devices described in US Patent Publication No. US20130177638, US20130177637, US20130177636, US20130177635, US20130177634, US20130177633, US20130183375, US20130183373 and US20130183372. In some embodiments, the liposomes are formed from 1,2-dioleyloxy-N,N- dimethylaminopropane (DODMA) liposomes, DiLa2 liposomes from Marina Biotech (Bothell, Wash.), 1,2-dilinoleyloxy-3-dimethylaminopropane (DLin-DMA), 2,2-dilinoleyl-4-(2- dimethylaminoethyl)-[1,3]-dioxolane (DLin-KC2-DMA), and MC3 (as described in US20100324120) and liposomes which can deliver small molecule drugs such as, but not limited to, DOXIL® from Janssen Biotech, Inc. (Horsham, Pa.). The polypeptide of polynucleotide of the present invention can be encapsulated by the liposome and/or it can be contained in an aqueous core which can then be encapsulated by the liposome (see International Pub. Nos. WO2012031046, WO2012031043, WO2012030901 and WO2012006378 and US Patent Publication No. US20130189351, US20130195969 and US20130202684). In some embodiments, the polynucleotide of the present invention is formulated with stabilized plasmid-lipid particles (SPLP) or stabilized nucleic acid lipid particle (SNALP) that have been previously described and shown to be suitable for oligonucleotide delivery in vitro and in vivo (see Wheeler et al. Gene Therapy.19996:271-281; Zhang et al. Gene Therapy.19996:1438- 1447; Jeffs et al. Pharm Res.200522:362-372; Morrissey et al., Nat Biotechnol.20052:1002- 1007; Zimmermann et al., Nature.2006441:111-114; Heyes et al. J Contr Rel.2005107:276- 287; Semple et al. Nature Biotech.201028:172-176; Judge et al. J Clin Invest.2009119:661- 673; deFougerolles Hum Gene Ther. 2008 19:125-132; U.S. Patent Publication No US20130122104). The original manufacture method by Wheeler et al. was a detergent dialysis method, which was later improved by Jeffs et al. and is referred to as the spontaneous vesicle formation method. The liposome formulations are composed of 3 to 4 lipid components in addition to the polynucleotide. As an example a liposome can contain, but is not limited to, 55% cholesterol, 20% disteroylphosphatidyl choline (DSPC), 10% PEG-S-DSG, and 15% 1,2- dioleyloxy-N,N-dimethylaminopropane (DODMA), as described by Jeffs et al. As another example, certain liposome formulations contain, but are not limited to, 48% cholesterol, 20% DSPC, 2% PEG-c-DMA, and 30% cationic lipid, where the cationic lipid can be 1,2- distearloxy-N,N-dimethylaminopropane (DSDMA), DODMA, DLin-DMA, or 1,2- dilinolenyloxy-3-dimethylaminopropane (DLenDMA), as described by Heyes et al. In some embodiments, the polynucleotide of the present invention is formulated in a lipid nanoparticle such as those described in International Publication No. WO2012170930. Lipid nanoparticle formulations typically comprise a lipid, in particular, an ionizable cationic lipid, and further comprise a neutral lipid, a sterol and a molecule capable of reducing particle aggregation, for example a PEG or PEG-modified lipid. The lipid can be selected from, but is not limited to, DLin-DMA, DLin-K-DMA, 98N12-5, C12-200, DLin-MC3-DMA, DLin-KC2- DMA, DODMA, PLGA, PEG, PEG-DMG, PEGylated lipids and amino alcohol lipids. In some embodiments, the lipid is a cationic lipid such as, but not limited to, DLin-DMA, DLin-D- DMA, DLin-MC3-DMA, DLin-KC2-DMA, DODMA and amino alcohol lipids. The amino alcohol cationic lipid can be the lipids described in and/or made by the methods described in US Patent Publication No. US20130150625. As a non-limiting example, the cationic lipid can be 2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,2Z)-octadeca-9,12-dien-1- yloxy]methyl}propan-1-ol (Compound 1 in US20130150625); 2-amino-3-[(9Z)-octadec-9-en- 1-yloxy]-2-{[(9Z)-octadec-9-en-1-yloxy]methyl}propan-1-ol (Compound 2 in US20130150625); 2-amino-3-[(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2- [(octyloxy)methyl]propan-1-ol (Compound 3 in US20130150625); and 2-(dimethylamino)-3- [(9Z,12Z)-octadeca-9,12-dien-1-yloxy]-2-{[(9Z,12Z)-octadeca-9,12-dien-1- yloxy]methyl}propan-1-ol (Compound 4 in US20130150625); or any pharmaceutically acceptable salt or stereoisomer thereof. Nanoparticle formulations of the present disclosure can be coated with a surfactant or polymer in order to improve the delivery of the particle. In some embodiments, the nanoparticle is coated with a hydrophilic coating such as, but not limited to, PEG coatings and/or coatings that have a neutral surface charge. The hydrophilic coatings can help to deliver nanoparticles with larger payloads such as, but not limited to, polynucleotides within the central nervous system. As a non-limiting example nanoparticles comprising a hydrophilic coating and methods of making such nanoparticles are described in US Patent Publication No. US20130183244. Administration of the polypeptides or polynucleotides of the present invention can be achieved in various ways, including oral, buccal, rectal, parenteral, intraperitoneal, intradermal, transdermal, intrathecal, nasal, intracheal, etc., administration. The active agent may be systemic after administration or may be localized by the use of regional administration, intramural administration, or use of an implant that acts to retain the active dose at the site of implantation. For example, one strategy for drug delivery through the blood brain barrier (BBB) entails disruption of the BBB, either by osmotic means such as mannitol or leukotrienes, or biochemically by the use of vasoactive substances such as bradykinin. The potential for using BBB opening to target specific agents is also an option. A BBB disrupting agent can be co- administered with the therapeutic compositions of the invention when the compositions are administered by intravascular injection. Other strategies to go through the BBB may entail the use of endogenous transport systems, including carrier-mediated transporters such as glucose and amino acid carriers, receptor-mediated transcytosis for insulin or transferrin, and active efflux transporters such as p-glycoprotein. Active transport moieties may also be conjugated to the therapeutic or imaging compounds for use in the invention to facilitate transport across the epithelial wall of the blood vessel. Alternatively, drug delivery behind the BBB is by intrathecal delivery of therapeutics or imaging agents directly to the cranium, as through an Ommaya reservoir. The invention will be further illustrated by the following figures and examples. However, these examples and figures should not be interpreted in any way as limiting the scope of the present invention. FIGURES: Figure 1 : Analysis of FHpl injection effects on hippocampus of APP/PS1 (6M) one month post-injection (presymptomatic time). Immunostaining experiments: (A.) One month post- injection, FHpl reduced not only the complement activation (MAC formation and C3a cleavage product) but also (B.) Aß deposits. Analysis effects of FHpl injection on inflammation (C.), neuronal cells survival (D.) and neurotransmitters secretion (E.) in APP/PS1 hippocampus versus APP/PS1 Pbs injected mice. Results will be expressed as the immunostaining intensity ± the standard error of the mean (SEM). Spatial frequency threshold across ages and genotype (C57BL/6J(WT) vs. APP/PS1 vs. APP/PS1 injected with FHpl or Pbs) will be analyzed by Mann-Whitney U test (GraphPad Software). P-values of 0.05 or less were considered significant. *, P<0.05; **,P<0.01;***,P<0.005 and NS=non-significant. N=3-6 mice. Scale bar=50µm. Gd=Gyrus Dente of hippocampus. Water Maze experiments: (F.) Injection of FHpl in APP/PS1 brain enhanced significantly the escape learning time, the quadrant and platform searching as well as the cumulative duration searching as compared to Pbs injected group. All statistical analysis will be performed with Graphpad Prism program. Data will be subjected to an analysis of variance (2-way ANOVA) followed by post hoc test. Values are expressed as mean ± SEM. P value < 0.05 was acknowledged for minimal significance level. Figure 2 : Immunostaining semi-quantitative analysis of FHpl injection effects on hippocampus of APP/PS1 -1, 3 and 6 months post injection (symptomatic time). Analysis effects of FHpl injection on inflammation markers expression (Il1ß, Il6, TNFα and MMR2), MAC and Aß deposits, neuronal cells survival (NeuN) and on neurotransmitters secretion (Psd95, Synapsin and VGLUT1) in APP/PS1 hippocampus versus Pbs injected APP/PS1 mice. Results will be expressed as the immunostaining intensity ± the standard error of the mean (SEM). Spatial frequency threshold across ages and treatment (APP/PS1 injected with FHpl or Pbs) will be analyzed by Mann-Whitney U test (GraphPad Software). P-values of 0.05 or less were considered significant..*, P<0.05; **,P<0.01;***,P<0.005 and NS=non-significant. N=5- 7 mice for each immunostaining. Figure 3 : Water Maze experiments analysis of FHpl injection effects on cognitive functions of APP/PS1 -1, 3 and 6 months after injection (symptomatic time). Injection of FHpl enhanced significantly the escape learning time, the quadrant and platform searching as well as the cumulative duration searching as compared to Pbs injected group at all times investigated. All statistical analysis will be performed with Graphpad Prism program. Data will be subjected to an analysis of variance (2-way ANOVA) followed by post hoc test. Values are expressed as mean ± SEM. P value < 0.05 was acknowledged for minimal significance level..*, P<0.05; **,P<0.01;***,P<0.005 and NS=non-significant. EXAMPLE: Methods Ethics for animal use All experiments were performed in accordance with the European Communities Council Directive 86/609/EEC and French national regulations. Adult APP /PS1 or APP/PS1-FH^-/- female mice and age matched wild type (WT) C57BL/6J control mice (Jackson Laboratory) at 3, 6,7, 9,10, 12 and 15 months of age were used. FH Ko (FH^-/-) mice come from Dr. Pickering and have been well characterized¹⁴. APP/PS1 transgenic mice overexpress hAPP with mutations linked to familial AD (Swedish and Indiana mutations) coupled to a mutant human presenilin (PS1-E9) yielding vast amount of Aβ plaques. Both mutations are associated with early-onset AD. These mice showed a useful amyloid phenotype of AD coupled with cognitive dysfunctions (symptomatic stage). They develop Alzheimer's disease-like amyloid β protein (Aβ) deposits around 9 months of age and show an age-dependent increase in the level of Aβ and in the number of amyloid plaques in the brain¹⁵. APP/PS1 mice develop Aβ deposits with a higher accumulation in females¹⁶. All mice used for this study were housed in the laboratory animal facility (agreement number: B33-318-701, ref.202003021406937 / APAFIS N°24555). Animals were kept under pathogen- free conditions with food and water ad libidum and litter. They were housed in a 12-hour/12- hour light/dark cycle. For all procedures involving tissue collection, mice were first anesthetized with isoflurane (Aerrane®, Baxter) and euthanized by cervical dislocation. FH injection: The mouse was anesthetized with a mixture of air and isofluorane (3% induction and 1.5% maintenance), the skull was shaved and the animal is placed on a stereotaxis frame (Stoelting) and the skin is incised over 1cm. A first injection of Buprenorphine (0.03 mg/kg) by subcutaneous way was carried out 30 min before the surgery then a second one 8 hours after the first. Stereotactic surgery: a hole is made in the skull at the level of the prefrontal medial cortex with an adapted drill. The injector is composed of a hamilton syringe lowered into the orifice. A solution containing or not FH (5μL diluted in a Pbs solution for a final concentration of 6μM) was infused, during 3 min then the injector is reassembled and the skull skin sutured. The stereotaxic coordinates for the injection were (relative to the bregma): 1 mm posterior, +/- 0.5 mm lateral and 2 mm ventral. Optical clearing: Organ pretreatment & MAC immunolabeling : iDISCO+ optical clearing protocol was adapted from¹⁷-¹⁸ protocols. Briefly, each mouse received a retroorbital intravenous 100 µL injection of lectin coupled to a fluorophore (Lycopersicon esculentum Lectin DyLight649® 1 mg/mL, Vector Labs, Eurobio Scientific, France) to stain the systemic capillary network. Ten minutes after the injection, an intraperitoneal 100 µL injection of isosorbide dinitrate was made to dilate the vessels. The mouse was then euthanized by an intraperitoneal injection of 300 µL sodium pentobarbital diluted in physiological saline solution. After death, a sternotomy was carried out to catheterize the heart left ventricle. A perfusion of physiological solution at 80 mm Hg pressure for 3 min was done to remove the blood from the vasculature. A second perfusion of 4% formalin was done to fix the tissues. The brain was delicately removed and placed in paraformalin overnight at 4 °C. The brain was dehydrated by successive immersions in 20%, 40%, 60%, 80%, 100% methanol solutions for 1 hour each at room temperature (RT), then left overnight at RT in 2/3 dichloromethane and 1/3 methanol solution. Bleaching was performed in 5% H2O2 and 95% methanol overnight at 4°C. The brain was rehydrated by successive immersions in 80%, 60%, 40%, 20%, methanol solutions, and Pbs for 1 hour each at RT. For immunolabeling, permeabilization was performed by incubating the brain in a permeabilization solution (Pbs Triton 0,5%) for 2 days at RT. Non-specific antigens sites were blocked by incubation in a blocking solution (Pbs/Triton 0,5%/ Normal goat serum 10%) for 3 days at RT. Immunolabeling steps were performed by incubating the brain in anti-C5b9 or MAC (1:200 dilution in Pbs/Triton0,5%, Santa Cruz) primary antibody solution for 7 days at 4°C under agitation, then in TRITC (Invitrogen, France, 1:250 dilution in Pbs/Triton0,5%) secondary antibody solution for 5 days at 4°C under agitation. The brain was treated by successive immersions in 20%, 40%, 60%, 80% methanol solutions for 1 hour each at room temperature, then left overnight in a pure methanol at RT. Permeabilization and lipid removal were then performed in a 2/3 dichloromethane and 1/3 methanol solution for 3 hours at RT. The remaining methanol was removed by two 15 min-baths in pure dichloromethane solutions at RT. Last, refractive index matching was done by leaving the sample in a dibenzyl ether solution for a few hours at RT, then kept at 4°C until imaging. Image acquisition (Light sheet microscopy) : Each brain was mounted in ethyl cinnamate solution in a specific device adapted to the light sheet microscope. The ultramicroscopy was done using the system from LaVision BioTec (Bielefeld, Germany) equipped with 545 and 640 nm laser lines, a sCMOS Andor camera, and a 0.5 NA 2X objective with a deeping lens, with 6.3 zoom. The tissue was illuminated laterally by three horizontal sheets. Exposition time was 200 ms. Emitted fluorescences were collected at 630 and 690 nm, respectively. At the end of the acquisition, the stack was automatically reconstructed in 16-bits format. Capillary network imaging was made by sampling of 1080 x 1280 x 300 µm parallelipipedic sections in the hyppocampus zone of the brain. The system spatial resolution was 1 µm (x, y) and 4 µm (z). Step size used was 2 µm. Voxel dimensions were 0.5 µm (x, y) and 2 µm (z). Western Blot analysis Brains were lysed in ice-cold lysis buffer (50 mM Tris-HCL, pH 7.5, 100 mM NaCl, 0.1 % NP- 40, 1% deoxycholate, 50 mM ß-glycerophosphate, 0.2 mM sodium orthovanadate, 50mM sodium fluoride, 1 µg/ml leupeptin, 5 µM pepstatin, 20 klU/ml aprotinin, 1 mM phenylmethylsulfonyl fluoride), and centrifuged for 10 minutes at 10,000 g at 4°C. Protein concentrations were determined by using a BCA kit. Brain lysates were mixed (N=5) with 5X Laemmli buffer and heated for 5 minutes at 95°C. They were then resolved by SDS-PAGE (10% polyacrylamide gels), electroblotted onto polyvinylidene difluoride (PVDF) membrane (Immobilon, Millipore, France), and probed with antibodies directed against the complement proteins C3/C3 fragments, FH and Actin (Table 1). After incubation with the secondary antibody donkey anti-rat or donkey anti-rabbit or donkey anti-goat conjugated to AlexaFluor 700 or AlexaFluor 800 (diluted 1:5000, Invitrogen, France), binding of antibodies was detected using the Odyssey Infrared Imaging System (LI-COR Biosciences, France). Protein loading quantity was controlled by using mouse monoclonal anti-ß actin antibodies (Cell Signaling, France) (Table1). Immunohistochemistry on mice brain To determine the expression level of the complement proteins C3, C3a, C5b-9 (MAC) and FH in the hippocampus of C57Bl/6J and APP/PS1, immunohistochemistry experiments were performed at 6,7, 9,10,12 and 15 months. The brains were removed just after death, were fixed in PFA4% -Pbs1X solution (overnight at 4°C), were cryoprotected in successive solutions of sucrose 10, 20 and 30% diluted in Pbs1X and finally were kept at -80°C until used. Transverse sections of animal brain were cut with a Microm HM550 cryostat (Microm, Walldorf, Germany) at -20°C, at a section thickness of 14 µm. The sections were mounted onto Polysine® glass slides (Polysine® Adhesion slides, Thermo Scientific, France) and stored at -80°C until processing. For staining, non-specific binding sites were blocked (10% normal house serum, 0,5% Triton X-100, in Pbs) for 1 hour at RT. The sections were incubated with primary antibodies overnight (Table 1). After washing in Pbs1X (3 times 10 minutes at RT), the sections were incubated with the secondary antibody donkey anti-rabbit, donkey anti-mouse, donkey anti-rat or donkey anti-goat conjugated to AlexaFluor 488, AlexaFluor 594 or AlexaFluor 643 (Invitrogen, France, diluted 1:500) as required, for 1 hour at RT. The sections were washed and mounted with fluorescent aqueous mounting medium containing DAPI (Dako, France). For semi-quantifications, images were acquired with confocal microscope (LSM 700 Carl Zeiss, France) using a 20x objective at a resolution of 1024x1024 pixels. Gain settings were at the same level when taking images for C57BL/6J and APP/PS1 tissue sections. Semi-quantification of the signal was performed using NIH ImageJ by a blinded investigator. Analysis of blood brain barrier permeability was realized by immunostaining experiments with an anti-albumin antibody, images were acquired with confocal microscope (LSM 700 Carl Zeiss, France) using a 63X/1.3 oil-immersion objective at the same resolution described above. N=5-7 mice. Water Maze: The Morris Water Maze (MWM) test is a widely used measurement of visuospatial memory and learning that has been demonstrated to have strong validity in investigation of cognitive effects of several brain disorders and of drugs used to treat cognitive deficits. The MWM test consists of a white circular pool (180 cm x 80 cm high) which was filled with water that is colored opaque with powdered non-fat milk to a depth of 35 cm, 26+/- 1°C. The pool is imaginarily divided into four equal compartments named A to D. A platform for escape was randomly placed on one of the four quadrants. At the first step, named visualization tests, the animals see the platform without external/extra-maze cues. The animals learn to find the visual platform more quickly. For the second step, the training, the platform is submerged 1cm below the surface of water and four visual cues with different shapes were randomly designated on north, south, east and west respectively. The mice must swim to the hidden escape platform. Then the mice were trained for 3 days starting at four different regions (A, B , C and D) of the pool each day. For each trial and mouse, latency time to find the submerged platform was recorded. If mice reached the platform in 60s, they stayed on it for 10s, if not, they were guided to the platform passively by the experimenter and were allowed to rest on the platform during 30s. On the protest session, mice were put at the B region (opposite of the ghost platform) and were allowed to navigate for 90s without platform only visual cues were let. The experiments were monitored by a video camera place above the middle of the pool. Latency time and cumulative duration were then recorded and analyzed. Statistics Immunostaining and Western Blot experiments: Results are expressed as the immunostaining intensity ± the standard error of the mean (SEM). Spatial frequency threshold across ages (6,7, 9,10, 12 and 15 months) and genotype (APP/PS1 vs. C57BL/6J or APP/PS1) were analyzed by Mann-Whitney U test (GraphPad Software). P-values of 0.05 or less were considered significant. Thus, in all figures, statistical significance is expressed as *P<0.05, **P<0.01, and ***P<0.001. For MWM experiments: Results are expressed in time to reach or search the visible or invisible platform. All statistical analysis were performed with Graphpad Prism program. Data were subjected to an analysis of variance (2-way ANOVA) followed by post hoc test. Values are expressed as mean ± SEM. P value < 0.05 was acknowledged for minimal significance level. Results: FH protects blood endothelial cells from overactivation complement induced lysis process We investigated the complement activation in APP/PS1 network vessels at late stage of the pathology (15 Months). Our experiments showed important deposits of activated complement marker MAC in / around and on the brain vessels (data not shown), suggesting vessel alterations could be induced by overactivation of complement. We also demonstrated the overactivation of complement by important levels of C3 and C3 cleaved fragment (C3a) on brain endothelial cells of APP/PS1 brain versus WT mice (data not shown). In addition, we showed that brain vessels lysed were associated with high concentration of MAC leading to albumin leakage (data not shown). In opposite, we observed no albumin vessels leakage in endothelial cells presented strong FH deposits associated with no MAC immunostaining (data not shown), suggesting that complement overactivation could participate to AD-breach vascular wall by MAC lysis function. Altogether these data suggested that FH accumulation on endothelial cells could prevent complement overactivation leading to blood vessel damages and AD. Dysregulation, impairment or inadvertent activation of complement fragments as well as its regulators contribute to the microenvironment inflammatory toxicity in brain. To determine the critical optimal stage of complement overactivation in APP/PS1 brain, we first evaluated the level of complement C3, its activated fragment (C3b) and its inhibitor FH using total brain protein extractions at 6 to 15 months, ages at which the vascular damages progress in this AD murine model¹⁶. We investigated complement activation by measuring the C3b concentration using an anti-C3 antibody which recognizes the alpha (α~115kDa), alpha cleaved chain (α’~110kDa) and the beta chain of C3 (ß~75kDa) (data not shown). The ratio of C3- α’cleaved chain / C3- ß chain represents the production of C3b while the ratio C3- α chain/C3- ß chain represents not cleaved C3. As compared to WT mice (C57BL/6J), we found a constant higher concentration of not cleaved C3 in the brain of APP/PS1 versus WT mice at all stages studied (data not shown). Concerning C3b, we observed also a higher production in brain of APP/PS1 mice versus WT with a maximum observed at 9 months (data not shown), suggesting an optimal complement activation system at 9 months in the brain of APP/PS1mice. C3b increased concentration was accompanied with an up-production of FH in the brain of APP/PS1 between 6 and 9 M but significantly decreased between 9 and 15 months (data not shown), suggesting a slight inhibition of complement in the later stages. In the hippocampus tissue, the major target of AD, we observed a high level of activated-complement MAC since 6 months with an optimum at 9 months associated with a decrease of FH concentration between 9 and 15 months in APP/PS1 versus WT mice, which was consistent with an overactivation of complement (data not shown). In parallel with overactivation of complement, our data showed an increase of Aβ deposits starting at 9 month-old in APP/PS1 hippocampus mice (data not shown). All together these data provided evidence that the overactivation of complement started at 6 months (presymptomatic stage) before the deposits of Aβ and was optimal at 9 months (symptomatic stage) in hippocampus of APP/PS1 despite increase FH level between 6 to 9 months. Based on these results, we hypothesized that inducing a high concentration of FH could decrease complement activation at early (presymptomatic: 6 Months) as well as late (symptomatic: 9 Months) stages and thus protects the hippocampus from irreversible damage leading to AD cognitive impairments. To proof the therapeutic effect of FH to treat AD, we have injected a human FH plasmatic (FHpl) into the cerebrospinal fluid (CSF) of APP/PS1 mice at two stages of AD development : presymptomatic stage (6M) and symptomatic stage (9M) (data not shown). Then, we investigated the FHpl effects on APP/PS1- Aβ deposits, - inflammation, survival cell death, -neurotransmitter levels and -cognitive functions at 1, 3 or 6 months post-injection. Human FHpl was chosen since APP/PS1 mice express two mutated human transgenes and this protein contains all expected human glycosylations. A final concentration of 6µM of FHpl was chosen in view of our previous results obtained for the treatment of laser-induced age-related macular degeneration in mice¹¹. We have chosen to inject into the CSF to avoid the blood brain barrier (BBB) function which is impermeable to large molecules such as FH (155kDa). The ependymal cells, which constitute the ventricles and ducts carrying the CSF, present tight junctions only on the choroidal plexuses interface and looser junctions for the other regions of brain which increase its exchanges with cerebral tissues. In addition, a systemic injection may lower the host’s immune defenses. At first, we have confirmed with a CSF-Evans blue injection that the FHpl-stereotaxic coordinates targeted the left lateral ventricle (data not shown). Secondly, we showed that FH-HisTag diffused into the hippocampus and cortex regions of APP/PS1 at 24 hours and one-month post-injection (data not shown). In contrast, no more FH-HisTag was detected after 3 months post-injection (data not shown). Finally, we showed that the injection of human FH-HisTag in brain of WT mice did not lead to cognitive dysfunctions (data not shown). FH transiently improves cognitive functions of AD-APP/PS1 mice during early stage In one month post-injection APP/PS16 month-old, FHpl reduced significantly the complement activation observed by a decreased of both C3a and MAC levels in the hippocampus of APP/PS1 mice (Figure 1A), demonstrating that human FHpl was active on mice complement activation system. Compared to APP/PS1 injected with Pbs, we observed also a significantly decrease of Aβ deposits in FH-injected mice at 7 months (Figure 1B). In addition, we demonstrated that FHpl injection modulated inflammation microenvironment by a decrease of TNF-α, IL6 and Il1β levels in hippocampus compared to APP/PS1 Pbs injected (Figure 1C). Furthermore, our results showed an increase of macrophages (type 2 : MMR2) infiltration in APP/PS1 FHpl-treated compared to Pbs treated groups (Figure 1C). The NeuN immunostaining showed no difference between APP/PS1 mice FH or Pbs injected (Figure 1D). Concerning neurotransmitter levels, we showed a significantly increase of VGLUT 1 and Psd95 concentrations in APP/PS1 FHpl treated compared to Pbs treated mice (Figure 1E). The FHpl- effects on inflammation and neurotransmitters levels lead to cognitive functions improvements. Indeed, we observed a better learning in APP/PS1 mice injected with FHpl, with notably an ability to find the platform more quickly after 3 days of learning than mice injected with Pbs (Figure 1F). In addition, FHpl-injected APP/PS1 mice found promptly the aera of the platform and spent more time searching for this ghost platform than Pbs injected mice (Figure 1F, Table 2), suggesting that FH significantly improved spatial memory in APP/PS1 mice. These data were in concert with an improvement of neurotransmitters secretion observed in APP/PS1 mice aged of 6 months and one month post-injected. Three months after FHpl injection in APP/PS1 mice, despite a decrease of Aβ and MAC concentrations we didn’t observe anymore improvement of neurotransmitters secretion and cognitive functions associated with no modulation of inflammatory microenvironment as compared to Pbs injected mice (Table 2). Altogether, our results clearly demonstrated a transient therapeutic effect of FH in AD treatment during early stage. FH improves the cognitive functions of APP /PS1 mice during late stages We confirmed human FHpl complement inhibition activity in mice by observing a decrease of C3a levels in APP/PS1 (9M) FH injected (1M post-injection) mice versus Pbs injected animals (data not shown). As previously observed, a decrease of Aβ and MAC deposits were also measured in APP/PS1 FHpl vs Pbs injected mice at all post-injection stages analyzed (Figure 2), confirming a role of FH on Aß accumulation and complement activation. One, three or six months after FHpl injection in 9-month-old APP/PS1 mice, our results showed a significantly decrease of TNFα and Il1β levels in the hippocampus region compared to Pbs-injected mice experimental groups (Figure 2). We also noted that immunostaining of IL6 decreased only one month after FHpl injection in APP/PS1mice compared with other post-injection times (Figure 2), suggesting a specific inflammatory microenvironment. In parallel, only at 3 month post- injection time, we noted a significant increase of MMR2 macrophages infiltration in FHpl APP/PS1 injected mice compared to Pbs injected groups (Figure 2). For all post-injection times tested, no effect on neuronal cells survival (NeuN immunostaining) was observed in APP/PS1 FHpl injected groups compared to Pbs injected mice (Figure 2). Furthermore, for 1M and 3M but not for 6M post-injected times, we observed higher Psd95 and VGLUT1 concentrations in hippocampus region of FHpl injected mice compared to Pbs (Figure 2). All together these data clearly showed a specific hippocampus microenvironment dependent on the FHpl injection time analysis. In accordance with a reduction in inflammatory response associated or not with neurotransmitters secretion improvement, FHpl enhanced significantly the escape learning time, the quadrant and platform searching as well as the cumulative duration searching as compared to Pbs injected or APP/PS1 group (Figure 3, Table 2). Nevertheless, we observed maximum cognitive functions improvements (cumulative duration) after 3 months post injection with ∼90% compared to 36% and 30% respectively for 1 and 6 months post injection time (Table 2). All these data confirm the therapeutic effect of FH on AD including symptomatic treatment. Deletion of FH expression accelerates loss of cognitive functions in APP/PS1 mice As we showed that FHpl injection improved cognitive functions in APP/PS1 mice at both early (6 months) and late injection stages (9 months), we investigated the effects of FH expression invalidation in memory of APP/PS1-FHko mice. Our results showed that since 3 months of age, APP/PS1 mice lacking the expression of FH had more difficulty in learning to find the platform than APP/PS1 mice expressing FH (data not shown). However, the APP/PS1-FHko mice presented the same platform quadrant escape latency time as APP/PS1 mice (data not shown), on the other hand, they took longer escape time to reach the ghost platform and found it less in the allotted time compared to APP/PS1 mice (data not shown), demonstrating that the loss of FH expression accelerated the AD pathology. As the APP/PS1 mice, at 7 months APP/PS1- FHko mice ended up losing their memory capacity to quickly find the platform compared to WT mice at the same age (data not shown), however, with higher problem to find the quadrant escape for APP/PS1-FHko compared to APP/PS1 mice (data not shown). At 9 and 12 month- old, both APP/PS1-FHko and APP/PS1 mice lost cognitive functions in the same way (data not shown). The invalidation of FH expression in healthy mice had no effect on cognitive functions (data not shown), demonstrating that non-expression of FH had only an aggravating effect in AD pathological environment. Discussion: This current study is the first to evaluate the effects of a single FH injection on AD’s processes : inflammation, Aß deposits, neuronal cells survival, neurotransmitters secretions and cognitive functions. We have shown that complement overactivation appeared weakly at 6 months and reached a peak at 9 months in the hippocampus of APP/PS1 mice. The concentration of FH decreased at 9M corresponding both to the peak of complement overactivation and when high Aß deposits appeared in APP/PS1 brain¹⁵. We have also shown that on brain vessels the uncountable of FH, in contrast to MAC deposits, lead to albumin leakage, suggesting a FH protection role to small vessels disease. In this context, our results clearly showed that a single FH-injection at early (6M) or even at late (9M) AD stages improved APP/PS1 cognitive functions by increasing neurotransmitters secretion and by decreasing Aß deposits, complement activation and cytokines release, demonstrated that FH would be a good target to treat Alzheimer disease. Toxic Aß aggregates are commonly found in cortical blood vessels as cerebral amyloid angiopathy^19,20. Usually, these deposits are also associated with inflammation which is an important element of AD pathogenesis with significant neurodegenerative disorders. Chronic inflammation was proposed as a dysregulated mechanism in AD patient²¹. Concomitant with these data, we observed on/in and around APP/PS1 brain vessels MAC deposits associated with vessel leakage, suggesting a role plaid by overactivation of complement on AD brain vessels damages. The inflammatory mediators interleukin IL1β, IL6 and TNF-α have been implicated in AD. Mechanisms underlying early neuronal dysfunctions and transient synaptic hyperexcitability involve the increase of TNF-α during the pre-symptomatic stage of AD^22–24. The increased of TNF-α level in the hippocampus is associated with neuroinflammation and memory impairment process in AD mouse models^22,25. Several lines of evidence using genetic and pharmacological manipulations indicate that cytokines like TNF-α signaling exacerbates Aβ pathologies in vivo²⁶ and causes C3 induction which could be cleaved inducing complement overactivation²⁷. In line with a potential therapeutic target of FH to treat AD, we observed a decrease of TNF-α level associated with less Aß deposits, suggesting a control by FH on TNF- α effects. IL1β also appears to play a major role in AD pathogenesis. IL1β has been reported to increase amyloid precursor protein²⁸ and exacerbates Tau phospohorylation²⁹, two important markers of AD progression. Blocking IL1β signaling rescues cognition in an Alzheimer's disease mice model (3xTg-AD mice)³⁰. In line with a beneficial role of FH on AD pathogenesis, we showed that FH injection was able to decrease IL1β secretion in APP/PS1 mice. IL6 is an AD component of early stage amyloid plaque formation³¹ and has been implicated in synapse loss in hippocampal neurons³² and learning deficits in mice³³. Neutralization of IL6 in the brain of AD mouse models rescued memory deficits³⁴. Previous meta-analyses have shown that IL6 is increased in CSF and plasma of AD patients compared to control individuals³⁵. Altogether, these data suggest a real link between IL6 and AD pathogenesis. In this study, we showed an early significant decrease of IL6 level after FH injection in hippocampus of APP/PS1 mice, suggesting a beneficial role of FH by reducing IL6 signaling on AD effects. Our findings establish regulated complement system by FH as a key mechanism linking inflammation regulation and AD pathogenesis. Complement inhibition by FH decreases the inflammatory response associated with AD, whether FH would be injected in the early or late stage of this pathology. However, a single injection of FH, during the inflammatory period preceding the symptoms of AD, no longer exerts any beneficial effects 3 months after injection, suggesting that the complement inhibition AD beneficial effects is transient and would require another injection. AD is characterized morphologically by a loss of synapses and of synaptic markers in cortical and hippocampal regions^36–38. Synapses loss has been reported to appear very early in AD brain and correlates strongly with cognitive dysfunctions. It has been suggested that alteration of neurotransmitters secretion is responsible for AD progression with an early degeneration of glutamatergic neurotransmission. Glutamate is the major excitatory neurotransmitter of the brain and is thus involved in learning and memory³⁹. Several studies have reported a reduction of glutamate levels in AD brain patients^40–42. Among the different forms of vesicular glutamate transporters (VGLUT), VGLUT1 is expressed in the hippocampus regions and is has been used as a glutamatergic terminal marker⁴³. The loss of VGLUT1 and VGLUT2 in frontal cortex is correlated with cognitive dysfunctions in AD⁴². Aß down-regulates VGLUT1 in AD thereby cause consequences for cognitive functions⁴⁴. Rodriguez -perdigon and collaborators suggested that progression of AD is exacerbated by abnormal regulation of VGLUT1⁴⁵. Our results showed that FH-injection in both early or late AD stage increased the concentration of VGLUT1, suggesting an enhanced glutamate transmission and thus a beneficial effect on Alzheimer's disease. Postsynaptic density protein 95 is the most important and abundant scaffolding protein of the postsynaptic membrane and regulates synaptic transmission and plasticity. Decrease level of Psd95 is observed in hippocampus from subjects with amnestic mild cognitive impairment⁴⁶, which appears as an aggravating factor to cognitive decline. In agreement with a beneficial effect of FH on secretion of neurotransmitters in AD, we detected a higher level of Psd95 after this injection. We showed for the first time that regulation of complement overactivation by FH-injection had promoted the secretion of some neurotransmitters known to be markers of AD progression, validating FH as a potential therapeutic target to treat AD. AD is a multifactorial disease. Complement dysfunction may be contributing to neurodegeneration decades before clinical symptoms in AD. It can be neurotoxic dependent on the level of activation and its effect on the pro-inflammatory cytokine secretion like IL6, IL1ß or TNF-α which release can result in the dysfunction of synapses and neuronal cell death leading to cognitive decline. In ageing mice, the C3 gene deficient mice present better learning and memory in hippocampus compared with their respective aged WT mice⁴⁷. Additionally, APP/PS1- C3^-/- mice present an abundance of Aß in late stage of AD and performed better in cognitive tasks compared with APP/PS1-C3^+/+ mice⁴⁸. A marked reduction in pro-inflammatory TNF-α despite the abundance of Aß is observed in APP/PS1-C3^-/- mice⁴⁹. Altogether, these data corroborate our results showing that inhibition of complement activation by FH-injection or C3 gene deficient expression undoubtedly has a beneficial effect on AD pathogenesis. The AD stage of inhibition of complement activation seems to be important to obtain longer term effects. A single injection of FH during the presymptomatic stage of AD-APP/PS1 mice model improved cognitive functions only over a transitory period, no effect was any more detected after 3 months post-injection. Surprisingly, at the symptomatic stage, the brain administration of FH improved the cognitive functions of APP/PS1 mice up to 6 months post injection. Altogether our data have suggested that the inhibition of complement activation should not occur too early otherwise its effects are limited or need an another injection. Unfortunately, there are still no really treatments available to stop the pathophysiological processes or even progression of AD⁵⁰. Our study opened the perspective to consider FH as a good therapeutic target to treat and slow down the progression of AD. Hence, in the current context of therapeutic research to treat AD, the regulation of complement activation could lead to the identification of a new drug molecule applicable to both early (presymptomatic time) and late (symptomatic time) stages of this pathology, unlike ongoing researches (Donanemab and Lecanemab)^4,5 which target only the Aß deposits generally effective only for patients presented mild cognitive impairment or at an early stage of the disease. In addition, regulating the inflammatory reaction of AD by reducing complement activation reduces not only the formation of Aß plaques but also damaging effects on synaptic transmission and on cognitive functions as our results have shown. Hence, this complement therapy could simultaneously reduce several processes responsible for worsening of AD in contrast to anti-Aß targeting strategies treatments. Finally, a major advantage of using FH is that this molecule is produced naturally by the organism and is therefore unlikely to be toxic, while the current use of antibodies specifically directed against Aß which induce oedema in brain patients. TABLES: Table 1: List of antibodies used for Western Blot and Immunostaining experiments. Table 2: Summary of FHpl injection effects (indicated in red) on APP/PS1 cognitive functions during both presymptomatic and symptomatic stages. REFERENCES: Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure. 1. Alzheimer’s disease - PubMed. https://pubmed.ncbi.nlm.nih.gov/20107219/. 2. Briggs, R., Kennelly, S. P. & O’Neill, D. Drug treatments in Alzheimer’s disease. Clin Med (Lond) 16, 247–253 (2016). 3. Schenk, D., Basi, G. S. & Pangalos, M. N. Treatment strategies targeting amyloid β- protein. 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Claims

CLAIMS: 1. A method of treating dementia in a patient in need thereof comprising administering to the patient a therapeutically effective amount of a factor H (FH) polypeptide or a polynucleotide encoding thereof wherein the patient to be treated is at a symptomatic stage of the disease and typically is at a dementia stage. 2. The method of claim 1 for the treatment of vascular cognitive impairment and dementia (VCID). 3. The method of claim 1 for the treatment of Alzheimer’s disease (AD). 4. The method of claim 3 for the curative treatment of AD. 5. The method according to any one of claims 1 to 4 wherein the FH polypeptide comprises or consists of an amino acid sequence having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue at position 19 to the amino acid residue at position 207 in SEQ ID NO:1. 6. The method according to any one of claims 1 to 4 wherein the FH polypeptide comprises or consists of an amino acid sequence having at least 80% of identity with the amino acid sequence that ranges from the amino acid residue at position 19 to the amino acid residue at position 1231 in SEQ ID NO:1. 7. The method according to any one of claims 1 to 6 wherein the polynucleotide is a messenger RNA (mRNA). 8. The method of claim 7 wherein the polynucleotide is inserted into a vector. 9. The method according to any one of claims 1 to 8 wherein the polypeptide or the polynucleotide is conjugated to at least one other molecule selected from the group consisting of polynucleotides, polypeptides, lipids, lectins, carbohydrates, vitamins, cofactors, and drugs. 10. The method according to any one of claims 1 to 9 wherein the polypeptide or the polynucleotide is formulated using one or more lipid-based structures that include but are not limited to liposomes, lipoplexes, or lipid nanoparticles.