Dysregulation of Multivesicular Body and Exosome Flux in Alzheimer's Disease

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Alzheimer's disease (AD) is a progressive and degenerative disorder of the brain. It is pathologically characterized by amyloid β (Aβ) plaques, neurofibrillary tangles (NFTs), and loss of neurons. The key events driving the pathogenesis in AD are not completely understood. The long-term objective of my research is to understand the molecular and cellular processes by which neurons respond to stress and how dysfunction of these responsive mechanisms contributes to neurodegenerative process. We propose to investigate a new molecular regulator of exosome biogenesis and its role in AD pathogenesis. Exosomes are extracellular microvesicles secreted by cells. Exosomes carry cargos including proteins, lipids, and RNAs to influence or alter the phenotype of the target cells. Exosomes may spread toxic molecules related to AD such as Aβ, APP, and tau. Modulating the level of exosomes has been shown to alter the load of Aβ plaques. Some of the basic components involved in exosome biogenesis are known and highly related to the endocytic pathway. The intraluminal vesicles (ILVs) of multivesicular bodies (MVBs) are the cellular source of exosomes. As MVBs fuse with the plasma membrane, ILVs are released into the extracellular space as exosomes. In contrast to studies on exosome cargos in AD, little is known if and how exosome biogenic machinery itself may be altered in response to the AD related pathogenic stress. We have studied the endosomal-lysosomal pathways including autophagy in neural stress response and their roles in neurodegenerative diseases, particularly AD and Parkinson's disease. With these efforts, we have unexpectedly discovered a novel role for vacuole membrane protein 1 (VMP1), which was previously shown to regulate autophagy peripheral cells, in exosome biogenesis in neural cells and its involvement in AD. Our preliminary findings support strongly the new hypothesis that VMP1 regulates the flux of MVB-exosome and -lysosome network in neurons. AD-associated pathogenic stress increases VMP1 to promote exosome biogenesis, and this impacts the ability of donor and recipient neurons to handle stress. We propose to use molecular as well as cellular approaches, AD transgenic animal, and postmortem human specimens to determine in Aim I whether VMP1 controls the flux of endosomal and lysosomal network and exosome biogenesis in neurons, and its underlying molecular mechanisms; in Aim II whether VMP1-mediated regulation of exosome biogenesis is altered in neurons under AD associated pathogenic stress; in Aim III whether dysregulation of VMP1-mediated exosome biogenesis occurs and underlies neuronal stress and pathology in a transgenic rat model of AD; and in Aim IV the status of VMP1 pathway in postmortem human AD brains. The study will significantly advance our understanding of the molecular mechanisms regulating exosome formation and reveal how the exosome biogenic process is targeted by AD associated stressors and its involvement in AD pathogenesis.