Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models

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.

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Publication Details

Journal
Neuron
Published
2026-04-01
DOI
https://doi.org/10.1016/j.neuron.2026.03.011
Primary Topic
Neuroinflammation and Neurodegeneration Mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models

Kelly Hartigan, B. Joon Kim, Mason D. Tate, Emma H. Doud et al.
Neuron
Neuroinflammation and Neurodegeneration Mechanisms
article

Deletion of SPI1 in microglia exacerbates amyloid pathology by impairing microglial response in Alzheimer’s disease models

Kelly Hartigan, B. Joon Kim, Mason D. Tate, Emma H. Doud, Sutha K. John, Luke C. Dabin, Sunwoo Chung, Dominic J. Acri, H. R. Sagara Wijeratne, Md. Mamun Al-Amin, Amber L. Mosley, Hande Karahan, Ahmad Daniel Sharify, Jungsu Kim, Justin R. Kim, Selena S. Wang
article en

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.

Neuron
Indiana University – Purdue University Indianapolis (US)
Alzheimer's Association, Eli Lilly and Company, Indiana University Foundation, National Institutes of Health, National Institute on Aging
Openalex Percentile: Top 32%
Neuroinflammation and Neurodegeneration Mechanisms
DOIOpen Access PDFOpenAlex
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