TY - JOUR
T1 - Loss of PILRA promotes microglial immunometabolism to reduce amyloid pathology in cell and mouse models of Alzheimer's disease
AU - Weerakkody, Tanya N.
AU - Sabelström, Hanna
AU - Andrews, Shan V.
AU - Chadarevian, Jean Paul
AU - Chin, Marcus Y.
AU - Tatarakis, David
AU - Propson, Nicholas E.
AU - Kim, Do Jin
AU - Theolis, Richard
AU - Parico, Gian Carlo G.
AU - Misker, Hiwot
AU - Kung, Jennifer E.
AU - Bandyopadhyay, Abira
AU - Robles Colmenares, Yaneth
AU - Jackson, Taggra-Nicole
AU - Qerqez, Ahlam N.
AU - Balasundar, Srijana
AU - Davis, Sonnet S.
AU - Ha, Connie
AU - Ghosh, Rajarshi
AU - Ravi, Ritesh
AU - Rana, Anil
AU - Germain, Kyla
AU - Tao, Arnold
AU - Xiong, Ken
AU - Braun, Dylan
AU - Raju, Karthik
AU - Huang, Kang-Chieh
AU - Zhan, Lihong
AU - Guo, Jing L.
AU - Safari Yazd, Hoda
AU - Sarrafha, Lily
AU - Capocchi, Joia Kai
AU - Hasselmann, Jonathan
AU - Chadarevian, Alina L.
AU - Tu, Christina
AU - Mansour, Kimiya
AU - Eskandari-Sedighi, Ghazaleh
AU - Tesi, Niccolò
AU - van der Lee, Sven
AU - Hulsman, Marc
AU - Oshegov, Georgii
AU - Pijnenburg, Yolande
AU - Calvert, Meredith
AU - Holstege, Henne
AU - Suh, Jung H.
AU - di Paolo, Gilbert
AU - Davtyan, Hayk
AU - Lewcock, Joseph W.
AU - Blurton-Jones, Mathew
AU - Monroe, Kathryn M.
PY - 2025/12/3
Y1 - 2025/12/3
N2 - 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 PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) 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. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA 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 PILRA-dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied PILRA KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.
AB - 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 PILRA G78R gene variant reduces AD risk in apolipoprotein E4 (APOE4) 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. PILRA knockout (KO) in iMG rescued ApoE4-mediated immunometabolic deficits and prevented lipotoxicity through increased lipid storage, improved mitochondrial bioenergetics, and antioxidant activity. PILRA 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 PILRA-dependent microglial functions. AD mice transplanted with human PILRA KO microglia exhibited reduced amyloid pathology and rescued synaptic markers. A high-affinity ligand blocking PILRA antibody phenocopied PILRA KO iMG. These findings suggest that PILRA is a pharmacologically tractable therapeutic target for AD.
UR - https://www.scopus.com/pages/publications/105023787625
U2 - 10.1126/scitranslmed.adw7428
DO - 10.1126/scitranslmed.adw7428
M3 - Article
C2 - 41337541
SN - 1946-6234
VL - 17
SP - eadw7428
JO - Science translational medicine
JF - Science translational medicine
IS - 827
ER -