| dc.description.abstract | Alzheimer′s disease (AD) is the most common form of
dementia in the elderly. Memory loss in AD is increasingly
attributed to soluble oligomers of the amyloid-b peptide
(AbOs), toxins that accumulate in AD brains and target
particular synapses. Glutamate receptors appear to be centrally
involved in synaptic targeting by AbOs. Once bound to
neurons, AbOs dysregulate the activity and reduce the surface
expression of both N-methyl-D-aspartate (NMDA) and 2-amino-
3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA) types
of glutamate receptors, impairing signaling pathways involved
in synaptic plasticity. In the extracellular milieu, AbOs promote
accumulation of the excitatory amino acids, glutamate and
D-serine. This leads to overactivation of glutamate receptors,
triggering abnormal calcium signals with noxious impacts on
neurons. Here, we review key findings linking AbOs to
deregulated glutamate neurotransmission and implicating this
as a primary mechanism of synapse failure in AD. We also
discuss strategies to counteract the impact of AbOs on
excitatory neurotransmission. In particular, we review evidence
showing that inducing neuronal hyperpolarization via
activation of inhibitory GABAA receptors prevents AbOinduced
excitotoxicity, suggesting that this could comprise a
possible therapeutic approach in AD. | |
