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The autophagy-lysosomal pathway is essential for neuronal homeostasis, and defects within this pathway have been directly linked to a growing number of neurodegenerative disorders including Alzheimer’s disease (AD). A key neuropathological feature of AD is cerebral accumulation of a 4-kDa peptide, termed amyloid β-peptide (Aβ), which is the principle component of senile plaques. Autophagy-lysosomal dysfunction is one of the main cellular defects contributing to the onset and progression of AD. Proper late endosome-lysosomal trafficking is essential for lysosomal maturation and autophagy-lysosomal degradation capacity. However, it is unclear if altered late endocytic trafficking leads to the aberrant increase of Amyloid Precursor Protein (APP) amyloidogenic processing, thereby resulting in the aberrant accumulation of Aβ. We have identified that Snapin acts as an adaptor linking late endosomes to the dynein motor and thus plays a key role in coordinating two dynamic processes: (1) dynein motor-driven retrograde transport of late endosomes; and (2) late endosomal-lysosomal membrane trafficking and lysosomal maturation. Such a mechanism enables neurons to maintain efficient degradation capacity, organelle function and cellular homeostasis via the autophagy-lysosomal pathway (Cai et al., 2010 Neuron; Cai and Sheng, 2011 Autophagy; Zhou and Cai et al., 2012 Cell Reports). Snapin deficiency in mouse results in reduced neuron viability, and neurodegeneration. Thus, our study elucidates a novel mechanism for up-regulating autophagy-lysosomal function through enhancing Snapin-mediated and dynein-driven late endosomal transport in neurons. Our research objective for this project is to define the role of up-regulated late endocytic trafficking and autophagy-lysosomal function in APP amyloidogenic processing and Aβ deposition, the key dynamic cellular processes directly linked to the neuropathology of AD. The central hypothesis for this study is that autophagy-lysosomal function is critical to regulate the activity of amyloidogenic machinery thus controlling Aβ production and senile plaque formation. The identified mechanisms are expected to ultimately provide new opportunities for developing preventive and therapeutic strategies that will benefit the growing numbers of AD patients who have either Aβ deposition or lysosomal pathology in the central nervous system.
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