Journal
NATURE NEUROSCIENCE
Volume 13, Issue 7, Pages 812-818Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.2583
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Funding
- Stephen D. Bechtel, Jr. Foundation
- US National Institutes of Health [AG022074, NS041787]
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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-beta (A beta) peptides have a causal role in its pathogenesis, but the underlying mechanisms remain uncertain. Here we discuss recent evidence that A beta 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 A beta assemblies depresses excitatory transmission at the synaptic level, but also triggers aberrant patterns of neuronal circuit activity and epileptiform discharges at the network level. A beta-induced dysfunction of inhibitory interneurons likely increases synchrony among excitatory principal cells and contributes to the destabilization of neuronal networks. Strategies that block these A beta effects may prevent cognitive decline in Alzheimer's disease. Potential obstacles and next steps toward this goal are discussed.
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