Wednesday, February 5, 2025
2/5/2025
Alzheimer’s disease (AD) is characterized by the presence of extracellular neuritic plaques and intraneuronal neurofibrillary tangles. In addition to amyloid plaques and neurofibrillary tangles, the presence of dystrophic neurites (DNs), referring to aberrant neuritic sprouting as well as swollen dendrites and/or axons, is known as one pathological feature in surrounding amyloid plaques on AD postmortem brains, and has been shown to correlate with cognitive dysfunctions in AD. With the increasing number of failures in clinical trials that target the formation of amyloid deposition, AD treatment is recognized to be extremely challenging. This study aims to explore the approach for preventing or reducing DNs. We have previously demonstrated that reticulon proteins, mainly RTN3 but not RTN1, are massively accumulated in DNs in surrounding neuritic but not diffuse amyloid plaques. RTN3+ DNs contain mainly clustered tubular endoplasmic reticulum (ER). To build around this finding, we have recently discovered through our various morphological characterizations that ATG9A‐positive DNs (ATG9A+ DNs) form near the core plaques while RTN3+ DNs form subsequently and can surround ATG9A+ DNs. ATG9A is a critical molecule required not only for pre‐autophagosome formation but also for autophagosome elongation and maturation. DNs, enriched with multibody vesicles and marked by the autophagy protein LC3 and RAB7 or ubiquitin, are usually distributed relatively farthest from the core amyloid plaque and develop the latest in our temporal study. In light of growing knowledge in this area, we propose to advance our study further by testing the hypothesis in this renewal application that aging and amyloid deposition induces ATG9A‐mediated abnormal trafficking and subsequent tubular ER clustering and autophagic dysfunctions in AD brains. Two specific aims are proposed to test this hypothesis: 1) Aim 1 is to investigate the effects of amyloid pathology on ATG9A trafficking and the underlying mechanism; 2) Aim 2 is to determine the role of microglia in mediating growth of dystrophic neurites in surrounding amyloid plaques. Overall, this renewal proposal has a set of readily achievable experiments that focus on the growth of various form of DNs and functional relationship between reticulon proteins and ATG9A in AD pathogenesis. We will also explore molecular targets for reducing or preventing formation of DNs for the ultimate purpose of improving cognitive functions. Such a study will yield critical knowledge that may guide therapeutic applications for decreasing DN formation and cognitive dysfunction in AD patients.
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