Role of Stabilization of MAMs and MAM-Associated Palmitoylated APP (MAM-palAPP) in Alzheimer’s Disease

Accumulating evidence from genetic, neuropathological, and longitudinal brain imaging studies strongly suggests that amyloid beta is the initial driver of Alzheimer’s disease (AD) neuropathogenesis. The most recent clinical successes of amyloid beta immunotherapy have reinforced the hypothesis that amyloid beta plays a major role in driving AD pathogenesis. Despite its promise, monoclonal antibody immunotherapy is not optimal owing to high costs and considerable safety concerns. As a result, there is now an urgent need to more comprehensively investigate all aspects of amyloid beta production to facilitate the development of small-molecule alternatives that can circumvent the challenges of amyloid beta immunotherapies. We have reported that a special membrane contact site juxtaposed between mitochondria and endoplasmic reticulum (ER), also known as MAMs (Mitochondria-Associated ER Membranes), are amyloid beta-generating hubs inside the axons that are long neuronal processes most proximal to synaptic degradation in AD. The primary objective of this proposal is to first determine the impacts of known and novel modulators of MAM stabilization on axonal and/or neuronal amyloid beta production from AD neurons, and next, to elucidate the underlying mechanism of the regulation of axonal or neuronal amyloid beta production upon modulation of MAM stabilization in axons. The outcome of our studies will provide insights into disease mechanisms and guide the development of novel therapeutic strategies aimed specifically at the amyloid beta-producing MAMs in axons.