Beyond Amyloid: Altered Gene Function in Neurodegenerative Diseases.

Our lab has focused on the function/dysfunction hypothesis in AD for nearly three decades. This hypothesis proposes that AD-linked mutations change critical functions of genes expressed in CNS, ultimately leading to disease pathogenesis. APP encodes Aβ precursor protein (APP), which is one of the genes we have studied because it is the Aβ precursor and pathogenic mutations in APP result in early-onset Familial AD. We have explored the synaptic functions of APP, with an emphasis on its role in synaptic vesicles (SV), after discovering that APP is present in SV, is highly enriched in presynaptic termini, and that it establishes an interactomic network with SV protein. We have identified two distinct domains of APP the cytosolic (JCasp) and intravesicular (ISVAID) domains that interact with SV proteins and modulate exocytosis. Specifically, interactions between SV proteins and the JCasp domain increase the release probability (Pr) of glutamatergic synapses [1], while interactions between SV proteins and the ISVAID domain decrease Pr [2].