Dynamin 1 and synaptic dysfunction in Alzheimer's disease

Alzheimer's disease (AD) is a progressive, neurodegenerative disorder that worsens as the affected individual ages and the brain pathology increases. The postmortem neuropathological markers of AD are senile plaques composed of beta-amyloid (Abeta) and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau. Another hallmark of AD is decreased synaptic density. It has been hypothesized that a stage of synaptic dysfunction precedes frank synapse loss, plaque accumulation, and tangle formation in AD. Importantly, one of the most critical synaptic proteins for synaptic vesicle endocytosis, dynamin 1, is reduced in the brains of AD patients. Thus, indicating that a reduction in dynamin 1 could be playing a central role in the pathogenesis of AD.; In this study we focused on the potential role of dynamin 1 in AD. In chapters one and two we provided introductory information and methodology, respectively. In chapter three, we showed that Abeta induced a significant decrease in dynamin 1, both in vitro and in vivo . This dynamin 1 decrease occurred in the absence of synapse loss and was likely the result of a calpain-mediated degradation of dynamin 1 protein and possibly the down-regulation of dynamin 1 gene expression. In chapter four, we showed that calpain activation was induced by sustained calcium influx mediated by N-methyl-D-aspartate receptors in cultured hippocampal neurons. In addition, we showed that soluble oligomeric Abeta, and not fibrillar Abeta, was responsible for this sustained calcium influx, calpain activation, and dynamin 1 degradation. Finally, in chapter five, we showed that Abeta caused ultrastructural changes indicative of impaired synaptic vesicle endocytosis in stimulated cultured hippocampal neurons. Our data also indicated that Abeta led to the accumulation of synaptic vesicle-associated proteins in membrane fractions from stimulated hippocampal neurons. Moreover, experiments using FM1-43 showed reduced dye uptake in stimulated hippocampal neurons treated with Abeta. Similar results were obtained with a dynamin 1 inhibitory peptide.; Collectively, our results identify a possible pathway to synaptic dysfunction in AD involving calcium dyshomeostasis, calpain activation, dynamin 1 degradation, and disruption of synaptic vesicle endocytosis in hippocampal neurons. This study also highlights the potential therapeutic benefits of calpain inhibition and NMDA receptor modulation in AD.