Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer’s disease
The Alzheimer's disease (AD) genetic landscape identified microglia as a key disease-modifying cell type. Paired immunoglobulin-like type 2 receptor alpha (PILRA) is an immunoreceptor tyrosine-based inhibitory motif domain-containing inhibitory receptor, expressed by myeloid cells such as microglia. The known protective <i>PILRA</i> G78R gene variant reduces AD risk in <i>apolipoprotein E4</i> (<i>APOE4</i>) carriers and is enriched in a cohort of healthy centenarians. However, mechanisms underlying protective effects in microglia are undefined. Here, we identified biological functions of PILRA in human induced pluripotent stem cell-derived microglia (iMG) and chimeric AD mice. <i>PILRA</i> knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. <i>PILRA</i> KO also enhanced microglial chemotaxis and attenuated inflammation. With pharmacological inhibitor studies, we showed that peroxisome proliferator-activated receptor and signal transducer and activator of transcription 1/3 mediated <i>PILRA</i>-dependent microglial functions. AD mice transplanted with human <i>PILRA</i> KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied <i>PILRA</i> KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.
Authors
- Lihong Zhan (ORCID: https://orcid.org/0000-0001-7772-9340)
- Gian Carlo G. Parico (ORCID: https://orcid.org/0000-0002-7110-403X)
- Marc Hulsman (ORCID: https://orcid.org/0000-0002-9889-3606)
- Rajarshi Ghosh (ORCID: https://orcid.org/0000-0002-5780-8241)
- Kathryn M. Monroe (ORCID: https://orcid.org/0000-0002-6901-1176)
- Abira Bandyopadhyay (ORCID: https://orcid.org/0009-0006-5906-0843)
- Nicholas E. Propson (ORCID: https://orcid.org/0000-0001-8205-3218)
- Ritesh Ravi (ORCID: https://orcid.org/0000-0001-7947-2585)
- Kang-Chieh Huang (ORCID: https://orcid.org/0000-0002-1538-2043)
- Hayk Davtyan (ORCID: https://orcid.org/0000-0001-8554-6456)
- Srijana Balasundar
- David Tatarakis (ORCID: https://orcid.org/0000-0001-6297-2321)
- Ken Xiong (ORCID: https://orcid.org/0000-0003-0334-7512)
- Sonnet S. Davis (ORCID: https://orcid.org/0000-0001-7189-1427)
- Ahlam N. Qerqez (ORCID: https://orcid.org/0000-0003-4694-5619)
- Jonathan Hasselmann (ORCID: https://orcid.org/0000-0003-2630-9850)
- Marcus Y. Chin (ORCID: https://orcid.org/0000-0002-7037-1603)
- Henne Holstege (ORCID: https://orcid.org/0000-0002-7688-3087)
- Richard Théolis (ORCID: https://orcid.org/0009-0005-9122-1451)
- Anil Rana (ORCID: https://orcid.org/0000-0002-5896-6380)
- Lily Sarrafha (ORCID: https://orcid.org/0000-0002-6168-2119)
- Shan V. Andrews (ORCID: https://orcid.org/0000-0001-5484-5306)
- Sven J. van der Lee (ORCID: https://orcid.org/0000-0003-1606-8643)
- Hanna Sabelström (ORCID: https://orcid.org/0000-0002-1736-7234)
- Jennifer E. Kung (ORCID: https://orcid.org/0000-0002-6784-7076)
- Mathew Blurton‐Jones (ORCID: https://orcid.org/0000-0002-7770-7157)
- Hoda Safari Yazd (ORCID: https://orcid.org/0000-0002-1555-7704)
- Joseph W. Lewcock (ORCID: https://orcid.org/0000-0003-3012-7881)
- Gilbert Di Paolo (ORCID: https://orcid.org/0000-0003-1032-1265)
- Yaneth Robles Colmenares
- Joia Kai Capocchi (ORCID: https://orcid.org/0000-0002-3433-5904)
- Jean Paul Chadarevian (ORCID: https://orcid.org/0000-0002-2478-6592)
- Ghazaleh Eskandari‐Sedighi (ORCID: https://orcid.org/0000-0003-0447-7722)
- Tanya Weerakkody (ORCID: https://orcid.org/0000-0001-6376-1649)
- Kyla Germain (ORCID: https://orcid.org/0000-0001-6250-320X)
- Meredith Calvert (ORCID: https://orcid.org/0000-0003-2893-959X)
- Hiwot Misker (ORCID: https://orcid.org/0009-0001-1730-783X)
- Do Jin Kim (ORCID: https://orcid.org/0000-0002-7078-3915)
- Jing Guo (ORCID: https://orcid.org/0000-0002-8503-3746)
- Connie Ha (ORCID: https://orcid.org/0000-0003-1257-2025)
- Yolande A.L. Pijnenburg (ORCID: https://orcid.org/0000-0003-2464-1905)
- C.- Y. Tu (ORCID: https://orcid.org/0009-0006-8353-4244)
- Niccoló Tesi (ORCID: https://orcid.org/0000-0002-1413-5091)
- Khaled Mansour (ORCID: https://orcid.org/0009-0000-9840-078X)
- Karthik Raju
- Arnold Tao
- Taggra-Nicole Jackson (ORCID: https://orcid.org/0009-0005-0917-5717)
- Jung H. Suh (ORCID: https://orcid.org/0000-0001-8119-326X)
- Dylan Braun (ORCID: https://orcid.org/0009-0007-1372-4736)
- Alina L Chadarevian
- Georgii Oshegov
Institutions
- University of California, Irvine (US)
- Denali Therapeutics (United States) (US)
- Amsterdam Neuroscience (NL)
- Vrije Universiteit Amsterdam (NL)
- Delft University of Technology (NL)
Publication Details
- Journal
- Science Translational Medicine
- Published
- 2025-12-03
- DOI
- https://doi.org/10.1126/scitranslmed.adw7428
- Citations
- 3
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 2.53