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

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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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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Correspondence to Jorge J Palop or Lennart 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 Neurosci 13, 812–818 (2010). https://doi.org/10.1038/nn.2583

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