PM20D1 Creates N-oleoyl-Leucine to Improve Clearance of Amyloid-β Aggregates by Microglia
Researchers here note a mechanism that encourages the innate immune cells known as microglia to better clear amyloid-β in the aging brain. The protein PM20D1 acts in the formation of N-acylamides, and generation of the product N-oleoyl-leucine encourages microglia to more efficiently remove amyloid-β aggregates. In animal models of Alzheimer's disease based on an excessive creation of amyloid-β aggregates this improves matters. As is usually the case, it remains to be seen as to whether this will help in the human condition; so far, clearance of amyloid-β via immunotherapies has not performed well, suggesting that it doesn't play as significant a role in the condition as hoped.
There is increasing evidence of microglia participation in Alzheimer's disease (AD), which incentives their modulation to intercept the disease. Here, we describe a new mechanism by which the recently AD-associated Peptidase M20 Domain Containing 1 (PM20D1) instructs microglia to tackle AD. We show that the PM20D1-derived N-oleoyl-Leucine (OLE) improves AD pathologies in two animal models of AD.
OLE induces microglia association with amyloid beta (Aβ) plaques, reduce their size, number and toxicity, and leads to enhanced neuroprotection and cognition. Furthermore, OLE also increases Aβ chemotaxis and clearance in microglia cultures and enhances cell viability in neurons subjected to AD-related stressors. Finally, we also find evidence for a PM20D1- and OLE-mediated microglia association with amyloid plaques and neuroprotection in human AD brains. In sum, our results provide further insight into the protective role of PM20D1 in AD and support the use of OLE as a microglia-modifying treatment for AD.