p75NTR proteolysis in Alzheimer's Disease

Columbia University Health Sciences, New York NY

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Abstract

DESCRIPTION (provided by applicant): Although pathogenic gene products in Alzheimer's disease (AD), i.e. amyloid beta-protein precursor (APP) and presenilins (PS), are expressed throughout the brain, early and most severe neurodegenerative changes in AD manifest in selective populations of neurons, specifically the neurons of the entorhinal cortex and basal forebrain. However, molecular mechanisms that underlie this selective vulnerability remain poorly understood. We have recently reported that the p75 neurotrophin receptor (p75NTR) undergoes PS-dependent APP-like proteolysis (1). The p75NTR is known to be expressed predominantly in AD vulnerable neurons and can affect neuronal survival by serving as a co-receptor for neurotrophins. Thus, we hypothesize that abberant processing of the p75NTR gives rise to p75NTR proteolytic derivatives that may contribute to selective dysfunction and/or degeneration of p75NTR-expressing neurons. Specific Aims are: 1) To examine the functional roles of p75-beta-p and p75-ICD fragments; 2) To determine the effects of PS mutations on proteolysis/signaling of the p75NTR.