Abstract Body

In several neurodegenerative disorders, including Alzheimer’s Disease (AD), synapses are affected early in the disease. Multiple mutations in APP and presenilin genes cause rare cases of familial AD, while the ApoE4 variant of the ApoE gene represents the strongest genetic risk factor for AD in the general population. APP and presenilin gene mutations are thought to induce AD pathogenesis by overproducing pathogenic Abeta variants, and ApoE4 is thought to influence Abeta clearance, but how Abeta might incite AD pathogenesis and how ApoE4 might predispose to AD pathogenesis remains incompletely understood. Moreover, compelling evidence implicates microglial and possibly astrocytic dysfunction in AD pathogenesis. In my lab, we have taken a cell-biological approach to these questions with a focus on synapses because of their prominent role in AD, recognizing that synapse impairments in AD may also be secondary to microglial dysfunction. We have examined how pathogenic APP mutations, chronic impairments of presenilin function, or ApoE4 may act on synapses, using human neurons trans-differentiated from ES and iPS cells as a model. Instead of searching for potential Abeta receptors –of which there are many– or studying the effects of ApoE4 on Abeta –which still remain unclear despite decades of study– we have examined the signaling induced by pathogenic mutant forms of APP, by inhibition of presenilins, or by ApoE. Our studies suggest that APP, presenilins, and ApoE4 act directly and dramatically on synapses, albeit in a differential manner, indicating that synapses may represent a common pathway for different genetic conditions promoting AD pathogenesis.