Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models
Year: 2026
Type: article
Abstract: Recent human genetic studies have highlighted the potential role of microglial genes and their regulatory functions in the pathogenesis of Alzheimer's disease (AD). The transcription factor PU.1 (encoded by SPI1) is expressed mainly in microglia in the central nervous system and has been reported to be a genetic risk factor for AD. However, the role of microglial SPI1 in AD etiology is still poorly understood. Here, we demonstrate that the selective deletion of Spi1 in microglia exacerbates AD-related pathologies in an amyloid mouse model. Specifically, microglial Spi1 deletion increases amyloid deposition, gliosis, and dystrophic neurites while decreasing the microglial response to plaques. By combining proteomics and functional analyses, we reveal that the loss of microglial Spi1 impairs phagocytosis through Syk, Lyn, and Fcgr1. Furthermore, directly activating these genes rescues the impaired amyloid-beta (Aβ) uptake caused by Spi1 knockdown, unveiling the potential mechanism of SPI1 in amyloid pathology.
Source: Neuron
Authors: Byungwook Kim, Mason Douglas Tate, Hande Karahan, H.R. Sagara Wijeratne, Ahmad Daniel Sharify, Selena S. Wang, Justin R. Kim, Justin R. Kim, Md. Mamun Al-Amin, Kelly Hartigan, Sunwoo Chung, Luke Child Dabin, Dominic J. Acri, Emma H. Doud, Sutha K. John, Amber L. Mosley, Jungsu Kim, Jungsu Kim
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $10,400
Awards: G1063740430, Role of MicroRNA-21 in Alzheimer's disease, G4350118794, Generation of Abi3 conditional knockout mouse model, G5973584631, The role of ABI3 in Alzheimers disease, The role of micro-RNA-33 in Tau pathology, G9000056510, G9000239869, Molecular genetic analyses of transcriptional dysregulation in Alzheimers disease, Proteomic and functional analysis of missense variants of APOE associated with Alzheimer disease risk
OpenAlex ID: W7146956682