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

Nature Neuroscience volume 13, pages 812818 (2010) | Download Citation

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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References

  1. 1.

    et al. Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models. Proc. Natl. Acad. Sci. USA 96, 3228–3233 (1999).

  2. 2.

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

  3. 3.

    et al. Naturally secreted oligomers of amyloid β protein potently inhibit hippocampal long-term potentiation in vivo. Nature 416, 535–539 (2002).

  4. 4.

    et al. APP processing and synaptic function. Neuron 37, 925–937 (2003).

  5. 5.

    et al. Synaptic activity regulates interstitial fluid amyloid-β levels in vivo. Neuron 48, 913–922 (2005).

  6. 6.

    et al. AMPAR removal underlies Aβ-induced synaptic depression and dendritic spine loss. Neuron 52, 831–843 (2006).

  7. 7.

    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).

  8. 8.

    et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer's disease. Neuron 55, 697–711 (2007).

  9. 9.

    et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science 321, 1686–1689 (2008).

  10. 10.

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

  11. 11.

    et al. Amyloid deposition is associated with impaired default network function in older persons without dementia. Neuron 63, 178–188 (2009).

  12. 12.

    & Epilepsy and cognitive impairments in Alzheimer disease. Arch. Neurol. 66, 435–440 (2009).

  13. 13.

    , & Alzheimer's disease. Lancet 368, 387–403 (2006).

  14. 14.

    Neuroscience: Alzheimer's disease. Nature 461, 895–897 (2009).

  15. 15.

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

  16. 16.

    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).

  17. 17.

    & The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297, 353–356 (2002).

  18. 18.

    & Twenty years of the Alzheimer's disease amyloid hypothesis: a genetic perspective. Cell 120, 545–555 (2005).

  19. 19.

    , & Apolipoprotein E4: a causative factor and therapeutic target in neuropathology, including Alzheimer's disease. Proc. Natl. Acad. Sci. USA 103, 5644–5651 (2006).

  20. 20.

    et al. The topography of grey matter involvement in early and late onset Alzheimer's disease. Brain 130, 720–730 (2007).

  21. 21.

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

  22. 22.

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

  23. 23.

    , & Targeting small Aβ oligomers: the solution to an Alzheimer's disease conundrum. Trends Neurosci. 24, 219–224 (2001).

  24. 24.

    & β oligomers – a decade of discovery. J. Neurochem. 101, 1172–1184 (2007).

  25. 25.

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

  26. 26.

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

  27. 27.

    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).

  28. 28.

    et al. A specific amyloid-β protein assembly in the brain impairs memory. Nature 440, 352–357 (2006).

  29. 29.

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

  30. 30.

    , , , & 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).

  31. 31.

    et al. Soluble oligomers of amyloid β protein facilitate hippocampal long-term depression by disrupting neuronal glutamate uptake. Neuron 62, 788–801 (2009).

  32. 32.

    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).

  33. 33.

    & Synapse loss in frontal cortex biopsies in Alzheimer's disease: correlation with cognitive severity. Ann. Neurol. 27, 457–464 (1990).

  34. 34.

    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).

  35. 35.

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

  36. 36.

    et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science 326, 1005–1007 (2009).

  37. 37.

    & Senile plaques in temporal lobe epilepsy. Acta Neuropathol. 87, 504–510 (1994).

  38. 38.

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

  39. 39.

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

  40. 40.

    , , & β-amyloid peptide activates α7 nicotinic acetylcholine receptors expressed in Xenopus oocytes. J. Biol. Chem. 277, 25056–25061 (2002).

  41. 41.

    et al. Mechanisms contributing to the deficits in hippocampal synaptic plasticity in mice lacking amyloid precursor protein. Neuropharmacology 38, 349–359 (1999).

  42. 42.

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

  43. 43.

    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).

  44. 44.

    & Long-term synaptic plasticity in hippocampal interneurons. Nat. Rev. Neurosci. 8, 687–699 (2007).

  45. 45.

    , , , & 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).

  46. 46.

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

  47. 47.

    et al. Role of NMDA receptor subtypes in governing the direction of hippocampal synaptic plasticity. Science 304, 1021–1024 (2004).

  48. 48.

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

  49. 49.

    , & A network dysfunction perspective on neurodegenerative diseases. Nature 443, 768–773 (2006).

  50. 50.

    & Does epileptiform activity contribute to cognitive impairment in Alzheimer's disease? Neuron 55, 677–678 (2007).

  51. 51.

    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. USA 100, 9572–9577 (2003).

  52. 52.

    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).

  53. 53.

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

  54. 54.

    , , & Neurobehavioral characterization of APP23 transgenic mice with the SHIRPA primary screen. Behav. Brain Res. 157, 91–98 (2005).

  55. 55.

    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).

  56. 56.

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

  57. 57.

    et al. Reducing endogenous tau ameliorates amyloid β-induced deficits in an Alzheimer's disease mouse model. Science 316, 750–754 (2007).

  58. 58.

    et al. Incidence and predictors of seizures in patients with Alzheimer's disease. Epilepsia 47, 867–872 (2006).

  59. 59.

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

  60. 60.

    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).

  61. 61.

    et al. Phenotype associated with APP duplication in five families. Brain 129, 2966–2976 (2006).

  62. 62.

    et al. Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain 133, 1143–1154 (2010).

  63. 63.

    & A prospective study of Alzheimer disease in Down syndrome. Arch. Neurol. 46, 849–853 (1989).

  64. 64.

    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).

  65. 65.

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

  66. 66.

    et al. GABAergic interneuron dysfunction impairs hippocampal neurogenesis in adult apolipoprotein E4 knockin mice. Cell Stem Cell 5, 634–645 (2009).

  67. 67.

    , , , & 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).

  68. 68.

    et al. Neuronal synchrony mediated by astrocytic glutamate through activation of extrasynaptic NMDA receptors. Neuron 43, 729–743 (2004).

  69. 69.

    & Astrocytes potentiate transmitter release at single hippocampal synapses. Science 317, 1083–1086 (2007).

  70. 70.

    , , & Synchronous hyperactivity and intercellular calcium waves in astrocytes in Alzheimer mice. Science 323, 1211–1215 (2009).

  71. 71.

    & Brain inflammation in epilepsy: experimental and clinical evidence. Epilepsia 46, 1724–1743 (2005).

  72. 72.

    , , & MAPK, beta-amyloid and synaptic dysfunction: the role of RAGE. Expert Rev. Neurother. 9, 1635–1645 (2009).

  73. 73.

    , , , & Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457, 1128–1132 (2009).

  74. 74.

    , & 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).

  75. 75.

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

  76. 76.

    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).

  77. 77.

    et al. Seizures and enhanced cortical GABAergic inhibition in two mouse models of human autosomal dominant nocturnal frontal lobe epilepsy. Proc. Natl. Acad. Sci. USA 103, 19152–19157 (2006).

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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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Affiliations

  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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Competing interests

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.

Corresponding authors

Correspondence to Jorge J Palop or Lennart Mucke.

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DOI

https://doi.org/10.1038/nn.2583