Journal
AGING AND DISEASE
Volume 6, Issue 2, Pages 131-148Publisher
INT SOC AGING & DISEASE
DOI: 10.14336/AD.2014.0423
Keywords
Beta-amyloid; tau; Alzheimer's disease; excitotoxicity; glutamate; NMDA; astrocytes; tripartite synapse
Categories
Funding
- National Institute of General Medical Sciences [U54GM104942]
- Alzheimer's Association [NIRG-12-242187]
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Alzheimer's disease (AD) is the most common form of dementia in individuals over 65 years of age and is characterized by accumulation of beta-amyloid (A beta) and tau. Both A beta and tau alter synaptic plasticity, leading to synapse loss, neural network dysfunction, and eventually neuron loss. However, the exact mechanism by which these proteins cause neurodegeneration is still not clear. A growing body of evidence suggests perturbations in the glutamatergic tripartite synapse, comprised of a presynaptic terminal, a postsynaptic spine, and an astrocytic process, may underlie the pathogenic mechanisms of AD. Glutamate is the primary excitatory neurotransmitter in the brain and plays an important role in learning and memory, but alterations in glutamatergic signaling can lead to excitotoxicity. This review discusses the ways in which both beta-amyloid (A beta) and tau act alone and in concert to perturb synaptic functioning of the tripartite synapse, including alterations in glutamate release, astrocytic uptake, and receptor signaling. Particular emphasis is given to the role of N-methyl-D-aspartate (NMDA) as a possible convergence point for A beta and tau toxicity.
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