Comparative profiling of the synaptic proteome from Alzheimer’s disease patients with focus on the APOE genotype

Degeneration of synapsesin Alzheimer9s disease (AD) strongly correlates with cognitive decline, and synaptic pathology contributes to disease pathophysiology. We recently discovered that the strongest genetic risk factor for sporadic AD, apolipoprotein Eepsilon 4 (APOE4), exacerbates synapseloss and synaptic accumulation of oligomeric amyloid betain human AD brain. To begin to understand the molecular cascades involved in synapseloss in AD and how this is mediated by APOE, and to generate a resource of knowledge of changes in the synaptic proteome in AD, we conducted a proteomic screen and systematic in-silico analysis of synaptoneurosome preparations from temporal and occipital cortices of human AD and control subjects with known APOE gene status. Our analysis identified over 5,500 proteins in human synaptoneurosomes and highlighted disease, brain region, and APOE-associated changes in multiple molecular pathwaysincluding a decreased abundance in AD of proteins important for synaptic and mitochondrial function and an increased abundance of proteins involved in neuroimmune interactions and intracellular signaling.