β-Amyloid-induced dynamin 1 depletion in hippocampal neurons -: A potential mechanism for early cognitive decline in Alzheimer disease

Synaptic dysfunction is one of the earliest events in the pathogenesis of Alzheimer disease ( AD). However, the molecular mechanisms underlying synaptic defects in AD are largely unknown. We report here that beta-amyloid ( A beta), the main component of senile plaques, induced a significant decrease in dynamin 1, a protein that is essential for synaptic vesicle recycling and, hence, for memory formation and information processing. The A beta-induced dynamin 1 decrease occurred in the absence of overt synaptic loss and was also observed in the Tg2576 mouse model of AD. In addition, our results provided evidence that the A beta-induced decrease in dynamin 1 was likely the result of a calpain-mediated cleavage of dynamin 1 protein and possibly the down-regulation of dynamin 1 gene expression. These data suggest a mechanism to explain the early cognitive loss without a major decline in synapse number observed in AD and propose a novel therapeutic target for AD intervention.