THE PM20D1-OLE PATHWAY INDUCES MICROGLIA REWIRING TO AMELIORATE ALZHEIMER DISEASE

Alzheimer’s disease (AD) is driven by the combination of genetic and environmental factors, leading to cognitive impairment, protein aggregate accumulation, and chronic neuroinflammation. We previously demonstrated that the epigenetic regulation of Peptidase M20 Domain Containing 1 (PM20D1) influences AD risk in humans and modulates disease progression in mouse models through mechanisms that remain incompletely understood. PM20D1 encodes an enzyme involved in the conjugation of N-oleoyl-leucine (OLE); however, it has remained unclear whether OLE itself confers protective effects in the context of AD. To test this, we treated multiple AD models with OLE and assessed associated behavioral and molecular changes. Our findings indicate that OLE exerts a protective role in AD by enhancing microglial association with amyloid plaques, resulting in reductions in plaque size, number, and toxicity, alongside improved neuroprotection and cognitive performance in AD mice. In vitro, OLE promotes amyloid chemotaxis and clearance in microglial cultures and increases neuronal survival under AD–related stress conditions. Notably, our data suggest that the beneficial effects of OLE may be mediated through the regulation of Cystatin C, pointing to this gene as a potential downstream effector of OLE action. Finally, we provide evidence supporting an OLE-dependent increase in microglial association with amyloid plaques and neuroprotection in human brain samples. Overall, these results provide new mechanistic insight into the protective function of PM20D1 in AD and support the potential of OLE as a microglia-modulating therapeutic strategy for the treatment of AD.