APP mimetic peptide as a potential therapeutic target to reduce amyloid generation

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Amyloid-β (Aβ) generation is a key pathological event in Alzheimer's disease (AD). Aβ is produced by the sequential proteolytic processing of the amyloid precursor protein (APP) by β- and γ- secretases. APP endocytosis is an important step in Aβ generation. APP is internalized to endosomes where APP is cleaved by β-secretase, initiating the amyloidogenic pathway. The sorting signal that regulates APP endocytic processing required for Aβ generation is the highly conserved endocytic YENPTY sequence located in the cytoplasmic region of APP. APP mice that lack the endocytic YENPTY motif have reduced APP internalization and lower brain Aβ levels. Through our studies, we found Mints (also known as APP binding family A, APBA) are a family of neuronal adaptor proteins that bind directly to the endocytic YENPTY motif of APP and are essential for regulating APP endocytosis and amyloidgenic processing. In addition, Mints interact with presenilin-1 (PS1), the catalytic core of the γ-secretase complex, facilitating APP-PS1 colocalization and promoting Aβ production. Further, we found that loss of any one of the three Mint proteins decreases Aβ production in aging mice and mouse models of AD. Together, we hypothesize that the APP-Mint interaction is a potential and novel therapeutic target to selectively reduce Aβ production in AD. We identified a novel cell-permeable APP mimetic peptide (TAT-APPMP) that interferes with the APP-Mint interaction. The TAT-APPMP is designed to outcompete endogenous APP binding to Mints to reduce Aβ production. Preliminary data reveals that treatment of primary neuronal cultures from an AD mouse model with TAT-APPMP reduced Aβ production with minimal toxicity. This provides compelling evidence that the APP-Mint interface is a viable therapeutic target for AD treatment and is expected to have strong translational implications. However, the biological characterization of the APPMP, examining its specificity, efficacy and its potential for in vivo AD treatment is lacking. The overall goal of this proposal is to determine the specificity of the cell-permeable APPMP to disrupt the APP-Mint interaction and reduce Aβ accumulation in AD mouse models.