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Nature Neuroscience
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Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks

Nature Neurosciencevolume 13, pages812–818 (2010)Cite this article

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Abstract

Alzheimer's disease is the most frequent neurodegenerative disorder and the most common cause of dementia in the elderly. Diverse lines of evidence suggest that amyloid-β (Aβ) peptides have a causal role in its pathogenesis, but the underlying mechanisms remain uncertain. Here we discuss recent evidence that Aβ may be part of a mechanism controlling synaptic activity, acting as a positive regulator presynaptically and a negative regulator postsynaptically. The pathological accumulation of oligomeric Aβ assemblies depresses excitatory transmission at the synaptic level, but also triggers aberrant patterns of neuronal circuit activity and epileptiform discharges at the network level. Aβ-induced dysfunction of inhibitory interneurons likely increases synchrony among excitatory principal cells and contributes to the destabilization of neuronal networks. Strategies that block these Aβ effects may prevent cognitive decline in Alzheimer's disease. Potential obstacles and next steps toward this goal are discussed.

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Figure 1: Presynaptic and postsynaptic regulation of synaptic transmission by Aβ.
Figure 2: Depression of excitatory synapses by high Aβ levels requires activation of mGluR- and NMDAR-dependent LTD pathways.
Figure 3: Pathologically elevated Aβ elicits abnormal patterns of neuronal activity in circuits and in wider networks in Alzheimer's disease–related mouse models.
Figure 4: Radiological evidence for aberrant activity in neuronal networks of humans with Alzheimer's disease.
Figure 5: Aβ-induced dysfunction of inhibitory interneurons could promote aberrant synchrony in neural networks.

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References

  1. Hsia, A.Y. et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models.Proc. Natl. Acad. Sci. USA96, 3228–3233 (1999).

    Article CAS  Google Scholar 

  2. Chapman, P.F. et al. Impaired synaptic plasticity and learning in aged amyloid precursor protein transgenic mice.Nat. Neurosci.2, 271–276 (1999).

    Article CAS  Google Scholar 

  3. Walsh, D.M. et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiationin vivo.Nature416, 535–539 (2002).

    Article CAS  Google Scholar 

  4. Kamenetz, F. et al. APP processing and synaptic function.Neuron37, 925–937 (2003).

    Article CAS  Google Scholar 

  5. Cirrito, J.R. et al. Synaptic activity regulates interstitial fluid amyloid-β levels in vivo.Neuron48, 913–922 (2005).

    Article CAS  Google Scholar 

  6. Hsieh, H. et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss.Neuron52, 831–843 (2006).

    Article CAS  Google Scholar 

  7. Shankar, G.M. et al. Natural oligomers of the Alzheimer amyloid-β protein induce reversible synapse loss by modulating an NMDA-type glutamate receptor-dependent signaling pathway.J. Neurosci.27, 2866–2875 (2007).

    Article CAS  Google Scholar 

  8. Palop, J.J. et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease.Neuron55, 697–711 (2007).

    Article CAS  Google Scholar 

  9. Busche, M.A. et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease.Science321, 1686–1689 (2008).

    Article CAS  Google Scholar 

  10. Minoshima, S. et al. Metabolic reduction in the posterior cingulate cortex in very early Alzheimer's disease.Ann. Neurol.42, 85–94 (1997).

    Article CAS  Google Scholar 

  11. Sperling, R.A. et al. Amyloid deposition is associated with impaired default network function in older persons without dementia.Neuron63, 178–188 (2009).

    Article CAS  Google Scholar 

  12. Palop, J.J. & Mucke, L. Epilepsy and cognitive impairments in Alzheimer disease.Arch. Neurol.66, 435–440 (2009).

    Article  Google Scholar 

  13. Blennow, K., de Leon, M.J. & Zetterberg, H. Alzheimer's disease.Lancet368, 387–403 (2006).

    Article CAS  Google Scholar 

  14. Mucke, L. Neuroscience: Alzheimer's disease.Nature461, 895–897 (2009).

    Article CAS  Google Scholar 

  15. Bertram, L. & Tanzi, R.E. Thirty years of Alzheimer's disease genetics: the implications of systematic meta-analyses.Nat. Rev. Neurosci.9, 768–778 (2008).

    Article CAS  Google Scholar 

  16. Farrer, L.A. et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis.J. Am. Med. Assoc.278, 1349–1356 (1997).

    Article CAS  Google Scholar 

  17. Hardy, J. & Selkoe, D.J. The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics.Science297, 353–356 (2002).

    Article CAS  Google Scholar 

  18. Tanzi, R.E. & Bertram, L. Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective.Cell120, 545–555 (2005).

    Article CAS  Google Scholar 

  19. Mahley, R.W., Weisgraber, K.H. & Huang, Y. Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease.Proc. Natl. Acad. Sci. USA103, 5644–5651 (2006).

    Article CAS  Google Scholar 

  20. Frisoni, G.B. et al. The topography of grey matter involvement in early and late onset Alzheimer's disease.Brain130, 720–730 (2007).

    Article  Google Scholar 

  21. Glabe, C.G. Structural classification of toxic amyloid oligomers.J. Biol. Chem.283, 29639–29643 (2008).

    Article CAS  Google Scholar 

  22. Selkoe, D.J. Soluble oligomers of the amyloid beta-protein impair synaptic plasticity and behavior.Behav. Brain Res.192, 106–113 (2008).

    Article CAS  Google Scholar 

  23. Klein, W.L., Krafft, G.A. & Finch, C.E. Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum.Trends Neurosci.24, 219–224 (2001).

    Article CAS  Google Scholar 

  24. Walsh, D.M. & Selkoe, D.J.A. β oligomers – a decade of discovery.J. Neurochem.101, 1172–1184 (2007).

    Article CAS  Google Scholar 

  25. Shankar, G.M. et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.Nat. Med.14, 837–842 (2008).

    Article CAS  Google Scholar 

  26. Cheng, I.H. et al. Accelerating amyloid-β fibrillization reduces oligomer levels and functional deficits in Alzheimer disease mouse models.J. Biol. Chem.282, 23818–23828 (2007).

    Article CAS  Google Scholar 

  27. Tomiyama, T. et al. A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo.J. Neurosci.30, 4845–4856 (2010).

    Article CAS  Google Scholar 

  28. Lesné, S. et al. A specific amyloid-β protein assembly in the brain impairs memory.Nature440, 352–357 (2006).

    Article  Google Scholar 

  29. Cleary, J.P. et al. Natural oligomers of the amyloid-β protein specifically disrupt cognitive function.Nat. Neurosci.8, 79–84 (2005).

    Article CAS  Google Scholar 

  30. Wang, Q., Walsh, D.M., Rowan, M.J., Selkoe, D.J. & Anwyl, R. Block of long-term potentiation by naturally secreted and synthetic amyloid β-peptide in hippocampal slices is mediated via activation of the kinases c-Jun N-terminal kinase, cyclin-dependent kinase 5, and p38 mitogen-activated protein kinase as well as metabotropic glutamate receptor type 5.J. Neurosci.24, 3370–3378 (2004).

    Article CAS  Google Scholar 

  31. Li, S. et al. Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake.Neuron62, 788–801 (2009).

    Article CAS  Google Scholar 

  32. Terry, R.D. et al. Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment.Ann. Neurol.30, 572–580 (1991).

    Article CAS  Google Scholar 

  33. DeKosky, S.T. & Scheff, S.W. Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity.Ann. Neurol.27, 457–464 (1990).

    Article CAS  Google Scholar 

  34. Mucke, L. et al. High-level neuronal expression of Aβ1–42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation.J. Neurosci.20, 4050–4058 (2000).

    Article CAS  Google Scholar 

  35. Wei, W. et al. Amyloid beta from axons and dendrites reduces local spine number and plasticity.Nat. Neurosci.13, 190–196 (2010).

    Article CAS  Google Scholar 

  36. Kang, J.E. et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle.Science326, 1005–1007 (2009).

    Article CAS  Google Scholar 

  37. Mackenzie, I.R. & Miller, L.A. Senile plaques in temporal lobe epilepsy.Acta Neuropathol.87, 504–510 (1994).

    Article CAS  Google Scholar 

  38. Abramov, E. et al. Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses.Nat. Neurosci.12, 1567–1576 (2009).

    Article CAS  Google Scholar 

  39. Puzzo, D. et al. Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus.J. Neurosci.28, 14537–14545 (2008).

    Article CAS  Google Scholar 

  40. Dineley, K.T., Bell, K.A., Bui, D. & Sweatt, J.D. β-amyloid peptide activates α7 nicotinic acetylcholine receptors expressed inXenopus oocytes.J. Biol. Chem.277, 25056–25061 (2002).

    Article CAS  Google Scholar 

  41. Seabrook, G.R. et al. Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein.Neuropharmacology38, 349–359 (1999).

    Article CAS  Google Scholar 

  42. Saura, C.A. et al. Loss of presenilin function causes impairments of memory and synaptic plasticity followed by age-dependent neurodegeneration.Neuron42, 23–36 (2004).

    Article CAS  Google Scholar 

  43. Laird, F.M. et al. BACE1, a major determinant of selective vulnerability of the brain to amyloid-beta amyloidogenesis, is essential for cognitive, emotional, and synaptic functions.J. Neurosci.25, 11693–11709 (2005).

    Article CAS  Google Scholar 

  44. Kullmann, D.M. & Lamsa, K.P. Long-term synaptic plasticity in hippocampal interneurons.Nat. Rev. Neurosci.8, 687–699 (2007).

    Article CAS  Google Scholar 

  45. Kim, J.H., Anwyl, R., Suh, Y.H., Djamgoz, M.B. & Rowan, M.J. Use-dependent effects of amyloidogenic fragments of β-amyloid precursor protein on synaptic plasticity in rat hippocampus in vivo.J. Neurosci.21, 1327–1333 (2001).

    Article CAS  Google Scholar 

  46. Snyder, E.M. et al. Regulation of NMDA receptor trafficking by amyloid-β.Nat. Neurosci.8, 1051–1058 (2005).

    Article CAS  Google Scholar 

  47. Liu, L. et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity.Science304, 1021–1024 (2004).

    Article CAS  Google Scholar 

  48. Tackenberg, C. & Brandt, R. Divergent pathways mediate spine alterations and cell death induced by amyloid-beta, wild-type tau, and R406W tau.J. Neurosci.29, 14439–14450 (2009).

    Article CAS  Google Scholar 

  49. Palop, J.J., Chin, J. & Mucke, L. A network dysfunction perspective on neurodegenerative diseases.Nature443, 768–773 (2006).

    Article CAS  Google Scholar 

  50. Leonard, A.S. & McNamara, J.O. Does epileptiform activity contribute to cognitive impairment in Alzheimer's disease?Neuron55, 677–678 (2007).

    Article CAS  Google Scholar 

  51. Palop, J.J. et al. Neuronal depletion of calcium-dependent proteins in the dentate gyrus is tightly linked to Alzheimer's disease-related cognitive deficits.Proc. Natl. Acad. Sci. USA100, 9572–9577 (2003).

    Article CAS  Google Scholar 

  52. Meilandt, W.J. et al. Enkephalin elevations contribute to neuronal and behavioral impairments in a transgenic mouse model of Alzheimer's disease.J. Neurosci.28, 5007–5017 (2008).

    Article CAS  Google Scholar 

  53. Minkeviciene, R. et al. Amyloid beta-induced neuronal hyperexcitability triggers progressive epilepsy.J. Neurosci.29, 3453–3462 (2009).

    Article CAS  Google Scholar 

  54. Lalonde, R., Dumont, M., Staufenbiel, M. & Strazielle, C. Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen.Behav. Brain Res.157, 91–98 (2005).

    Article CAS  Google Scholar 

  55. Kumar-Singh, S. et al. Behavioral disturbances without amyloid deposits in mice overexpressing human amyloid precursor protein with Flemish (A692G) or Dutch (E693Q) mutation.Neurobiol. Dis.7, 9–22 (2000).

    Article CAS  Google Scholar 

  56. Chin, J. et al. Fyn kinase induces synaptic and cognitive impairments in a transgenic mouse model of Alzheimer's disease.J. Neurosci.25, 9694–9703 (2005).

    Article CAS  Google Scholar 

  57. Roberson, E.D. et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model.Science316, 750–754 (2007).

    Article CAS  Google Scholar 

  58. Amatniek, J.C. et al. Incidence and predictors of seizures in patients with Alzheimer's disease.Epilepsia47, 867–872 (2006).

    Article  Google Scholar 

  59. Larner, A.J. & Doran, M. Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene.J. Neurol.253, 139–158 (2006).

    Article CAS  Google Scholar 

  60. Snider, B.J. et al. Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy bodies in the third decade of life.Arch. Neurol.62, 1821–1830 (2005).

    Article  Google Scholar 

  61. Cabrejo, L. et al. Phenotype associated withAPP duplication in five families.Brain129, 2966–2976 (2006).

    Article  Google Scholar 

  62. Jayadev, S. et al. Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2.Brain133, 1143–1154 (2010).

    Article  Google Scholar 

  63. Lai, F. & Williams, R.S. A prospective study of Alzheimer disease in Down syndrome.Arch. Neurol.46, 849–853 (1989).

    Article CAS  Google Scholar 

  64. Buckner, R.L. et al. Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory.J. Neurosci.25, 7709–7717 (2005).

    Article CAS  Google Scholar 

  65. Henry, T.R. & Votaw, J.R. The role of positron emission tomography with [18F]fluorodeoxyglucose in the evaluation of the epilepsies.Neuroimaging Clin. N. Am.14, 517–535 (2004).

    Article  Google Scholar 

  66. Li, G. et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice.Cell Stem Cell5, 634–645 (2009).

    Article CAS  Google Scholar 

  67. Yang, L., Wang, Z., Wang, B., Justice, N.J. & Zheng, H. Amyloid precursor protein regulates Cav1.2 L-type calcium channel levels and function to influence GABAergic short-term plasticity.J. Neurosci.29, 15660–15668 (2009).

    Article CAS  Google Scholar 

  68. Fellin, T. et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors.Neuron43, 729–743 (2004).

    Article CAS  Google Scholar 

  69. Perea, G. & Araque, A. Astrocytes potentiate transmitter release at single hippocampal synapses.Science317, 1083–1086 (2007).

    Article CAS  Google Scholar 

  70. Kuchibhotla, K.V., Lattarulo, C.R., Hyman, B.T. & Bacskai, B.J. Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice.Science323, 1211–1215 (2009).

    Article CAS  Google Scholar 

  71. Vezzani, A. & Granata, T. Brain inflammation in epilepsy: experimental and clinical evidence.Epilepsia46, 1724–1743 (2005).

    Article CAS  Google Scholar 

  72. Origlia, N., Arancio, O., Domenici, L. & Yan, S.S. MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE.Expert Rev. Neurother.9, 1635–1645 (2009).

    Article CAS  Google Scholar 

  73. Lauren, J., Gimbel, D.A., Nygaard, H.B., Gilbert, J.W. & Strittmatter, S.M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers.Nature457, 1128–1132 (2009).

    Article CAS  Google Scholar 

  74. Zhu, Y.J., Lin, H. & Lal, R. Fresh and nonfibrillar amyloid β protein(1–40) induces rapid cellular degeneration in aged human fibroblasts: evidence for AβP-channel-mediated cellular toxicity.FASEB J.14, 1244–1254 (2000).

    Article CAS  Google Scholar 

  75. Kayed, R. et al. Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer.J. Biol. Chem.284, 4230–4237 (2009).

    Article CAS  Google Scholar 

  76. Palop, J.J. et al. Vulnerability of dentate granule cells to disruption of Arc expression in human amyloid precursor protein transgenic mice.J. Neurosci.25, 9686–9693 (2005).

    Article CAS  Google Scholar 

  77. Klaassen, A. et al. Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy.Proc. Natl. Acad. Sci. USA103, 19152–19157 (2006).

    Article CAS  Google Scholar 

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Acknowledgements

This work was supported by a Stephen D. Bechtel, Jr. Foundation Young Investigator Award to J.J.P. and US National Institutes of Health grants AG022074 and NS041787 to L.M. We thank A. Kreitzer for comments on the manuscript and G. Howard and S. Ordway for editorial review.

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  1. Gladstone Institute of Neurological Disease and Department of Neurology, University of California, San Francisco, California, USA.,

    Jorge J Palop & Lennart Mucke

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Correspondence toJorge J Palop orLennart Mucke.

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L.M. has received research funding from Elan Pharmaceuticals and serves on the Scientific Advisory Boards of AgeneBio, Inc., iPierian, Inc. and Probiodrug A.G.

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Palop, J., Mucke, L. Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks.Nat Neurosci13, 812–818 (2010). https://doi.org/10.1038/nn.2583

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