Abstract
Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and neurodegeneration. Microglia, the resident immune cells of the central nervous system (CNS), play a crucial role in AD pathogenesis by containing the spreading of Aβ plaques. Genetic studies have associated a variant of the receptor Paired Immunoglobulin-like Type 2 Receptor Alpha (PILRα) with reduced risk for AD. PILRα is a receptor found on myeloid cells, such as microglia, that binds to endogenous cell surface glycoproteins and sends inhibitory signals within the cell. Additionally, it serves as an entry receptor for Herpes Simplex Virus 1. To elucidate the role of PILRα in microglial responses to brain pathology, here we used the cuprizone (CPZ) model of demyelination in Pilrα–/– mice. In this model, CPZ-fed mice experience oligodendrocyte death and demyelination of brain white matter, with microglia crucially clearing damaged myelin and promoting remyelination by oligodendrocyte progenitor cells (OPCs) after CPZ exposure ceases. Among mouse brain cells, PILRα expression was specifically observed in microglia. Deficiency of PILRα reduced microglia response to demyelination and myelin remodeling. This defect was associated with increased proliferation of OPCs. Co-immunoprecipitation experiments corroborated a direct interaction of PILRα with the inhibitory phosphatase SHP1. Hence, PILRα plays a key role in balancing the microglial response and promoting myelin regeneration by OPCs. This reveals an unexpected function in regulating repair mechanisms during brain pathology.
Committee Chair
Marco Colonna
Committee Members
Claudia Han; Fumihiko Urano; Gregory Wu; Michael Holtzman; Robert Schmidt
Degree
Doctor of Philosophy (PhD)
Author's Department
Biology & Biomedical Sciences (Molecular Cell Biology)
Document Type
Dissertation
Date of Award
4-9-2025
Language
English (en)
DOI
https://doi.org/10.7936/vvx2-rt89
Author's ORCID
https://orcid.org/0009-0001-1463-1909
Recommended Citation
Lin, Kent, "PILRα Sustains Microglial Capacity to Process Myelin in a Mouse Model of Demyelination" (2025). Arts & Sciences Theses and Dissertations. 3539.
The definitive version is available at https://doi.org/10.7936/vvx2-rt89