Role of OXR1 and the retromer in brain aging and Alzheimer's disease and related dementias - PROJECT SUMMARY/ABSTRACT Although some genetic risk factors for AD are known, the precise etiology of most cases of late-onset Alzheimer's disease (AD) is unknown. Unfortunately, AD therapies have been largely unsuccessful. Two important risk factors for AD, aging, and diet, remain poorly understood. Dietary restriction (DR), one of the most robust interventions to slow aging, also delays the onset of AD in multiple models across species. We exploited the short lifespan and powerful genetic tools in D. melanogaster to show that mustard (mtd)/oxidation resistance 1 (OXR1) is essential for DR-mediated lifespan extension. Importantly, mtd/OXR1 protects against age-related neurodegeneration in fly and human-induced pluripotent stem cell (iPSC)-derived models of neurodegenerative diseases. The mechanisms by which mtd/OXR1 protects against neurodegeneration remain unclear. However, we observed that Mtd/OXR1 directly binds retromer proteins, and inhibiting mtd reduces retromer proteins. Importantly, enhancing retromer function mitigates the harmful effects of mtd/OXR1 inhibition, reinforcing the hypothesis that retromer acts downstream of OXR1. We obsreved that OXR1 and other retromer proteins decline with age in humans and are associated with an increased risk of AD in humans, using proteomics data from over 2000 AD patients from the Accelerating Medicines Program–Alzheimer’s Disease network. Here, we will test the hypothesis that mtd/OXR1 enhances retromer function to slow aging and neurodegeneration in fly and human iPSC models of AD. In Aim 1, we will determine the role of specific retromer components in mediating the protective effects of mtd/OXR1. We will determine the downstream mechanisms (e.g., endocytic recycling, synaptic homeostasis, sphingoplipid, and aldehyde metabolism) by which mtd/OXR1 and retromer influence age-related neurodegeneration and aging. In Aim 2, we will determine the role of specific retromer components and the downstream targets of OXR1 in fly models of tauopathy. This will test how mtd/OXR1 modulates AD pathology in fly models that overexpress human tau. In Aim 3, we will overexpress OXR1 and retromer proteins in forebrain cholinergic and cortical neuron-derived AD iPSCs and measure AD endpoints. We will also determine if the retromer mediates the protective effects of mtd/OXR1 and if this regulation is conserved in human models of AD. By characterizing retromer function, protein networks regulated by mtd/OXR1, and their role in aging and age-dependent neurodegeneration, we will provide novel targets for developing therapeutics to slow AD-related pathologies and extend healthspan. With the proposed study, we will identify the conserved mechanisms by which mtd/OXR1 modulates retromer and synaptic homeostasis to influence lifespan and its neuroprotective effects in both fly and human iPSC-derived models of AD. These studies will have a significant impact on understanding how longevity-related pathways can be targeted to develop therapeutics for AD and related dementias.
