Effects of Depalmitoylation and ACAT Inhibition on Axonal Amyloid Beta Generation Via MAM-Associated palAPP

2021

Only 10% of amyloid precursor protein (APP) generates amyloid beta (Ab), one of the hallmarks of Alzheimer’s disease (AD) pathophysiology. Ten percent of total APP is palmitoylated-APP (palAPP), which serves as a better substrate for Ab generation. We recently reported that nearly all palAPP (more than 70%) resides in the region juxtaposed between the endoplasmic reticulum (ER) and the mitochondria called MAMs (mitochondria-associated ER membranes). We also have demonstrated that the disruption of MAMs in the axons and in neuronal processes leads to reduction in axonal Ab generation in a 3D cellular model of AD. MAMs are implicated in early- and late-onset AD, but their roles are largely unknown. We propose to demonstrate that small molecule depalmitoylating agents, such as hydroxylamine and its derivatives or inhibitors of MAM-resident ACAT1 enzymes, reduce Ab generation from axons or from neuronal processes by inhibiting the levels of MAM-associated palAPP (MAM-palAPP). The overarching goal is to generate mechanistic data to develop effective therapeutic strategies against AD by specifically targeting the MAM-palAPP in the axons or in neuronal processes.


Funding to Date

$172,500

Focus

Studies of APP and Abeta, Translational

Researchers

Raja Bhattacharyya, Ph.D.


Rudy Tanzi, Ph.D.