Post-synaptic scaffolding protein interactions with glutamate receptors in synaptic dysfunction and Alzheimer's...

Alzheimer's disease (AD) is characterized clinically by an insidious decline in cognition. Much attention has been focused on proposed pathogenic mechanisms that relate Aβ plaque and neurofibrillary tangle pathology to cognitive symptoms, but compelling evidence now identifies early synaptic loss and dysfunction, which precede plaque and tangle formation, as the more probable initiators of cognitive impairment. Glutamate-mediated transmission is severely altered in AD. Glutamate receptor expression is most markedly altered in regions of the AD brain that show the greatest pathological changes. Signaling via glutamate receptors controls synaptic strength and plasticity, and changes in these parameters are likely to contribute to memory and cognitive deficits in AD. Glutamate receptor expression and activity are modulated by interactions with post-synaptic scaffolding proteins that augment the strength and direction of signal cascades initiated by glutamate receptor activity. Scaffold proteins offer promising targets for more focused and effective drug therapy. In consequence, interest is developing into the roles these proteins play in neurological disease. In this review we discuss disruptions to excitatory neurotransmission at the level of glutamate receptor-post-synaptic scaffolding protein interactions that may contribute to synaptic dysfunction in AD.