Friday, May 9, 2025
5/9/2025
Mechanisms and therapeutic potential of the autophagy-lysosome pathway in Alzheimer’s disease - Project Summary/Abstract The overall objectives of this proposal are to elucidate novel mechanisms underlying the regulation of the transcription Factor EB (TFEB) and autophagy-lysosomal pathway (ALP), and to investigate their therapeutic potential as mechanism-based treatments for Alzheimer’s disease (AD). Genetic evidence indicates that dysfunction of ALP contributes to the pathogenesis of AD. Furthermore, TFEB, a master regulator for lysosomal and autophagic biogenesis, has been shown to mitigate AD progression in AD mouse models. Our preliminary studies demonstrate that two protein phosphatases, CDC25A and PP2A, regulate TFEB signaling and downstream ALP pathway and Tau clearance. Importantly, we found that inhibition of CDC25A activates TFEB in an AMPK-mediated manner; that inhibition of lysosomal acidic ceramidase (ASAH1) enhances PP2A activity, thus leading to TFEB activation; and that a combined inhibition of ASAH1 and CDC25A activates TFEB synergistically. Therefore, we hypothesize that CDC25A and PP2A play important roles in the regulation of endolysosomal and autophagic network via modulating TFEB, and that inhibition of CDC25A and ASAH1 can promote the clearance of Tau aggregates for AD treatment. In this proposal, we will elucidate the mechanisms underlying the regulation of TFEB and lysosomal autophagic function by CDC25A/AMPK and ASAH1/PP2A signaling. We will also examine the role and therapeutic implication of targeting CDC25A/AMPK and ASAH1/PP2A signaling axis in AD pathogenesis and treatment. Interdisciplinary techniques including chemical biology, proteomics, genomics, iPSC-based neuron differentiation, and mouse modeling for AD pathogenesis will be used for this mechanistic and preclinical investigation. Success of the proposed research will lead to an in-depth mechanistic understanding of the regulation of TFEB and ALP and achieve the proof-of principle of potential therapeutic strategies for AD treatment by targeting CDC25A and ASAH1, alone or in combination. Further, beyond Tau pathology, this study can be expanded in the future to APP/Aβ pathology in AD.
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