doi: 10.4103/NRR.NRR-D-23-01403. Epub 2024 Jul 29.
Decoding molecular mechanisms: brain aging and Alzheimer's disease
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- PMID:39104174
- PMCID: PMC11759015
- DOI: 10.4103/NRR.NRR-D-23-01403
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Decoding molecular mechanisms: brain aging and Alzheimer's disease
Mahnoor Hayat et al. Neural Regen Res..
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Abstract
The complex morphological, anatomical, physiological, and chemical mechanisms within the aging brain have been the hot topic of research for centuries. The aging process alters the brain structure that affects functions and cognitions, but the worsening of such processes contributes to the pathogenesis of neurodegenerative disorders, such as Alzheimer's disease. Beyond these observable, mild morphological shifts, significant functional modifications in neurotransmission and neuronal activity critically influence the aging brain. Understanding these changes is important for maintaining cognitive health, especially given the increasing prevalence of age-related conditions that affect cognition. This review aims to explore the age-induced changes in brain plasticity and molecular processes, differentiating normal aging from the pathogenesis of Alzheimer's disease, thereby providing insights into predicting the risk of dementia, particularly Alzheimer's disease.
Copyright © 2025 Copyright: © 2025 Neural Regeneration Research.
Conflict of interest statement
Figures
Similarities and differences in molecular and cellular changes in aging brains under normal conditions (green color) and in the pathogenesis of AD (red color). The figure uses green color to depict the molecular and cellular changes that occur under non-pathological conditions in the aging brain. These changes indicate the natural progression of aging and its impact on brain function, while red highlights specific molecular and cellular changes in AD pathogenesis, including the accumulation of amyloid plaques, tau protein tangles, and neuroinflammation. Created using Adobe Illustrator 2020 (24.3). AD: Alzheimer’s disease; Aβ: amyloid-beta; NFTs: neurofibrillary tangles.
A progressive timeline of pathological changes in the brain and stages of AD. In AD, cellular pathology occurs with the formation of amyloid beta plaques and neurofibrillary tangles, followed by synaptic dysfunction, inflammation, neuronal cell death, cerebral atrophy, and vascular changes, collectively leading to severe cognitive impairment and brain atrophy (Tse and Herrup 2017; Kim and Chung 2021). Created using Adobe Illustrator 2020 (24.3). AD: Alzheimer’s disease; Aβ: amyloid-beta; MCI: mild cognitive impairment.
Processing of APP contributes to the pathogenesis of Alzheimer’s disease. In the non-amyloidogenic pathway, APP is cleaved by α-secretase, yielding extracellularly released soluble APP (left). In the amyloidogenic pathway, APP is cleaved by β-secretase, followed by γ-secretase (right). This process leads to the release of extracellular Aβ, which is prone to self-aggregation, ultimately resulting in the formation of cytotoxic oligomers and insoluble Aβ fibrils/plaques (Syed et al. 2024). Created using Adobe Illustrator 2020 (24.3). AICD: APP intracellular domain; APP: amyloid precursor protein; Aβ: amyloid-beta.
The pathological process of tau pathology in Alzheimer’s disease. The hyperphosphorylation (denoted as “P”) of the tau protein leads to the destabilization of the tau–tubule complex and the assembly of the tau protein into higher-order aggregates. Hyperphosphorylated tau detaches from microtubules and aggregates to form paired helical filaments and neurofibrillary tangles (Syed et al. 2024). Created using Adobe Illustrator 2020 (24.3).
Genetic spectrum of rare to common variants contributing to the AD risk. The figure illustrates the intricate relationship between genetics and AD. Based on their susceptibility risk factors, the orange, blue, and light green circles represent genes linked to AD risk, while the gene labels inside the red circle highlight established AD risk genes, encompassing both rare mutations like those in PSEN1 and PSEN2 that cause the early onset of AD and the common APOE4 variant, which significantly increases risk. While the green circle in the figure depicts risk loci, containing chromosomal regions linked to an increased risk of AD, which contains multiple genes, unlike specific genes depicted in other colored circles (Guerreiro et al., 2013; Karch and Goate, 2015). Created using Adobe Illustrator 2020 (24.3). AD: Alzheimer’s disease; APOE: apolipoprotein E; APP: amyloid precursor protein; PSEN: presenilin-1; TREM: triggering receptors expressed on myeloid cells.
PI3K/Akt signaling pathway and Alzheimer’s disease. Growth factors (e.g., BDNF, platelet-derived growth factor, insulin-like growth factor, and epidermal growth factor) stimulate a cascade of signal transduction events, which include Akt, PI3K, and PLCγ. Upon binding, growth factors autophosphorylates tyrosine residues in the intracellular C-terminal domain, subsequently triggering the activation of second messenger signaling pathways, such as PLCγ, MAPK, and PI3K, which are essential for the synthesis of CREB. Active GSK-3 is associated with Alzheimer’s disease pathology including tau phosphorylation, formation of Aβ plaques, poor memory, microglia activation, and synaptic plasticity (Syed et al. 2024). These abnormal pathways are associated with pathological processes of Alzheimer’s disease. Created using Adobe Illustrator 2020 (24.3). Aβ: Amyloid-beta; BDNF: brain-derived neurotrophic factor; CaM: calmodulin; CaMK: Ca2+/calmodulin-dependent protein kinase; CREB: cAMP-response element binding protein; DAG: diacylglycerol; GSK-3: glycogen synthase kinase 3; IP3: inositol trisphosphate; MAPK: mitogen-activated protein kinase; PI3K: phospoinositide 3-kinase; PLC: phospholipase C.
JAK/STAT signaling pathway in Alzheimer’s disease. Ligand binding activates JAKs through receptor juxtaposition, triggering autophosphorylation of specific tyrosine (TYR) sites. Subsequently, phosphorylated JAKs catalyze the phosphorylation of STAT proteins, leading to the formation of protein dimers via SH2 domains. These dimers translocate into the nucleus, promoting gene transcription and inducing cellular responses, such as proliferation or survival. Created using Adobe Illustrator 2020 (24.3). JAK: Janus kinase; PIAS: protein inhibitor of activated STAT; PTP: protein tyrosine phosphatase; STAT: signal transducer and activator of transcription.
IRE1 signaling pathway of the unfolded protein response (UPR) in AD. Abnormal protein misfolding triggers ER stress signaling, leading to the phosphorylation of elF2α, which impairs synaptic function and cognitive processes. The IREIα pathway enhances amyloid deposition, resulting in AD. While XBP1 is a major regulator of UPR, it protects against Aβ toxicity and controls gene expression related to AD (Adams et al. 2019). Created using Adobe Illustrator 2020 (24.3). AD: Alzheimer’s disease; APP: amyloid precursor protein; ATF4: activating transcription factor 4; eIf2α: eukaryotic initiation factor 2 alpha; ER: endoplasmic reticulum; GCN2: general control nonderepressible 2; IRE1α: inositol requiring enzyme 1 alpha; ISRIB: integrated stress response inhibitor; PERK: protein kinase R-like endoplasmic reticulum kinase; PKR: protein kinase R; XBP1: X-box binding protein 1.
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