Polarity determinants in endolysosomal trafficking and proteostasis: Implications for Alzheimer's disease pathogenesis

内溶酶体运输和蛋白质稳态中的极性决定因素：对阿尔茨海默病发病机制的影响

• 批准号: 9912086
• 负责人: Huaye Zhang
• 金额: $ 19.88万
• 依托单位: RBHS-ROBERT WOOD JOHNSON MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912086
• 关键词: Abeta clearance; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease risk; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Autophagocytosis; Autophagosome; Axon; Biochemical; Cell Polarity; Characteristics; Color; Complement; Complex; Data; Defect; Dendrites; Disease Progression; Distal; Epithelial; Epithelium; Fluorescent Probes; Frequencies; Generations; Hippocampus (Brain); Human; Image; Knockout Mice; Knowledge; Laboratories; Lead; Light; Link; Lysosomes; Malignant Neoplasms; Measures; Molecular; Nerve Degeneration; Neurons; Pathogenesis; Pathogenicity; Pathway interactions; Peptides; Permeability; Process; Prosencephalon; Proteins; Research; Risk Factors; Role; Signal Transduction; Synaptosomes; Testing; Time; Vacuole; Western Blotting; abeta accumulation; age related; aging brain; beta secretase; beta-site APP cleaving enzyme 1; conditional knockout; confocal imaging; gamma secretase; imaging study; in vivo; middle age; neuron development; novel; novel therapeutics; optogenetics; presenilin-1; proteostasis; stem; stem cell division; trafficking

Project Summary The vast majority of Alzheimer’s disease (AD) is sporadic, with aging being the biggest risk factor. Yet age-related changes within neurons that can drive the AD pathogenic process remain elusive. Intriguingly, there is an intricate link between the aging process and cell polarity. Dysregulation of polarity is observed in many cellular contexts during aging, such as increased permeability of epithelial barriers, defective asymmetric division of stem cells and increased frequency of cancer. However, whether brain aging and Alzheimer’s disease result from polarity dysregulation is unknown. Research in our laboratory has focused on the partitioning defective (Par) polarity proteins in neuronal development and degeneration. Interestingly, our recent studies point to a key role for Par3 in the pathogenesis of AD. AD is characterized by plaques composed of β-amyloid (Aβ), which is derived from amyloid precursor protein (APP) through cleavage by β- and γ-secretases. The rate-limiting step of Aβ generation is the convergence between APP and its β-secretase BACE1. We found Par3 expression is significantly reduced by middle-age, and loss of Par3 is common in human AD brains. In addition, Par3 depletion causes a significant increase in APP and BACE1 convergence. Unexpectedly, we found Aβ accumulates intracellularly in the absence of Par3. Further studies suggest this is caused by defective autophagosome clearance. Remarkably, accumulation of autophagosomes and other autophagic vacuoles is also characteristic of the AD brain. Thus, these exciting data have led to our hypothesis that loss of Par3 in the aging brain promotes AD progression by targeting both APP/BACE1 convergence and autophagy. Dysregulation of these processes will lead to intracellular Aβ accumulation, which is highly toxic to neurons. We will test our hypothesis through two aims. In Aim 1, we will elucidate the mechanism by which Par3 regulates APP and BACE1 convergence and intracellular Aβ accumulation. In Aim 2, we will examine the mechanism by which Par3 regulates autophagy and lysosome functions. We will use a combination of BiFC, optogenetic manipulation of Par protein activity, as well as in vivo analysis in forebrain- specific Par3 conditional knockout mice. Together, our proposed studies will establish the molecular mechanisms by which Par polarity proteins are involved in AD pathogenesis. The results will shed light on the mechanism of sporadic AD in which aging is the major risk factor and polarity dysregulation may be the common feature.

项目总结