The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease

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.

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Publication Details

Journal
Cell Death and Disease
Published
2026-04-27
DOI
https://doi.org/10.1038/s41419-026-08791-1
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease

Johan Auwerx, Mahmood Haj‐Yahya, José V. Sánchez‐Mut, Johannes Gräff et al.
Cell Death and Disease
Neuroinflammation and Neurodegeneration Mechanisms
article

The PM20D1-OLE pathway induces microglia rewiring to ameliorate Alzheimer disease

Johan Auwerx, Mahmood Haj‐Yahya, José V. Sánchez‐Mut, Johannes Gräff, Aida Giner de Gracia, Fatima Gunter-Rahman, Liliane Glauser, Allison M. Burns, Mario Romani, Hilal A. Lashuel, Alejandro González-Ramón, Victoria Pozzi-Ruiz, Rajasekhar Kolla
article en

Abstract

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.

Cell Death and Disease
Instituto de Neurociencias (ES), École Polytechnique Fédérale de Lausanne (CH)
National Science Foundation, EU Joint Programme – Neurodegenerative Disease Research, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, European Regional Development Fund, Agencia Estatal de Investigación
Openalex Percentile: Top 6%
Neuroinflammation and Neurodegeneration Mechanisms
DOIOpen Access PDFOpenAlex
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