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.

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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. ,

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Transition Award (R00)
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Special Emphasis Panel (NSS)
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Refolo, Lorenzo
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Rutgers University
Anatomy/Cell Biology
Schools of Arts and Sciences
New Brunswick
United States
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Lin, Mei-Yao; Cheng, Xiu-Tang; Tammineni, Prasad et al. (2017) Releasing Syntaphilin Removes Stressed Mitochondria from Axons Independent of Mitophagy under Pathophysiological Conditions. Neuron 94:595-610.e6
Feng, Tuancheng; Tammineni, Prasad; Agrawal, Chanchal et al. (2017) Autophagy-mediated Regulation of BACE1 Protein Trafficking and Degradation. J Biol Chem 292:1679-1690
Tammineni, Prasad; Cai, Qian (2017) Defective retrograde transport impairs autophagic clearance in Alzheimer disease neurons. Autophagy 13:982-984
Cai, Qian; Tammineni, Prasad (2017) Mitochondrial Aspects of Synaptic Dysfunction in Alzheimer's Disease. J Alzheimers Dis 57:1087-1103
Ye, Xuan; Feng, Tuancheng; Tammineni, Prasad et al. (2017) Regulation of Synaptic Amyloid-? Generation through BACE1 Retrograde Transport in a Mouse Model of Alzheimer's Disease. J Neurosci 37:2639-2655
Tammineni, Prasad; Jeong, Yu Young; Feng, Tuancheng et al. (2017) Impaired axonal retrograde trafficking of the retromer complex augments lysosomal deficits in Alzheimer's disease neurons. Hum Mol Genet 26:4352-4366
Tammineni, Prasad; Ye, Xuan; Feng, Tuancheng et al. (2017) Impaired retrograde transport of axonal autophagosomes contributes to autophagic stress in Alzheimer's disease neurons. Elife 6:
Ye, Xuan; Sun, Xiaqin; Starovoytov, Valentin et al. (2015) Parkin-mediated mitophagy in mutant hAPP neurons and Alzheimer's disease patient brains. Hum Mol Genet 24:2938-51
Ye, Xuan; Cai, Qian (2014) Snapin-mediated BACE1 retrograde transport is essential for its degradation in lysosomes and regulation of APP processing in neurons. Cell Rep 6:24-31
Sheng, Zu-Hang; Cai, Qian (2012) Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci 13:77-93

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