The autophagy-lysosomal pathway is essential for neuronal homeostasis. Defects within this pathway have been directly linked to a growing number of neurodegenerative diseases. Lysosomal dysfunction is one of the main cellular defects contributing to the onset and progression of Alzheimer's Disease (AD). However, it is unclear if altered late endocytic trafficking leads to the aberrant increase of Amyloid Precursor Protein (APP) amyloidogenic processing, and thereby results in the accumulation of Amyloid p-peptide (Ap) in patient brains. The goal of this work is to define the role of an up-regulated late endocytic pathway in APP processing and Ap accumulation during the onset and progression of AD. My central hypothesis is that autophagy-lysosomal function is a critical step required to regulate the activity of the amyloidogenic machinery and, thus, control Ap deposition in AD brains. Using mouse genetic and cell biological approaches combined with gene rescue experiments in live neurons, we established that Snapin coordinates retrograde transport of late endosomes and membrane trafficking ofthe late endocytic pathway, thus highlighting a novel mechanism for up-regulating neuronal autophagy-lysosomal function. The contribution of this study is expected to advance our knowledge and provide mechanistic insights into how Snapin-mediated up-regulation of late endosome-lysosomal trafficking controls APP metabolism and Ap deposition, and eliminates damaged mitochondria in the brain of AD models. The identified mechanisms are expected to provide new concepts leading to preventive and therapeutic strategies that will benefit the growing number of AD patients who have either Ap deposition or lysosomal pathology and mitochondrial dysfunction in the central nervous system. It is expected that the findings from the proposed study will ultimately be applicable to the prevention and treatment of many age-related neurodegenerative diseases associated with the accumulation of protein aggregates and dysfunctional lysosomes and mitochondria. This work is consistent with the longstanding commitment ofthe NIA to understand the aging process and fight age-related neurodegenerative diseases.
The results from the proposed study will substantially advance our understanding of the mechanisms regulating neuronal autophagy-lysosomal function, which may provide the molecular and cellular basis for translational research in the development of novel therapeutic strategies to rescue dysfunctional neurons and arrest, or even reverse, the disease process of AD and other neurodegenerative diseases. ,
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