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Updated: Jun 18, 2026
Detection of Neuritic Plaques in Alzheimer's Disease Mouse Model
Published on: July 26, 2011
Sustained microglial depletion with CSF1R inhibitor impairs parenchymal plaque development in an Alzheimer's disease
Elizabeth Spangenberg1, Paul L Severson2, Lindsay A Hohsfield1
1Department of Neurobiology and Behavior, University of California Irvine (UCI), Irvine, CA, 92697, USA.
Abstract:
Many risk genes for the development of Alzheimer's disease (AD) are exclusively or highly expressed in myeloid cells. Microglia are dependent on colony-stimulating factor 1 receptor (CSF1R) signaling for their survival. We designed and synthesized a highly selective brain-penetrant CSF1R inhibitor (PLX5622) allowing for extended and specific microglial elimination, preceding and during pathology development. We find that in the 5xFAD mouse model of AD, plaques fail to form in the parenchymal space following microglial depletion, except in areas containing surviving microglia. Instead, Aβ deposits in cortical blood vessels reminiscent of cerebral amyloid angiopathy. Altered gene expression in the 5xFAD hippocampus is also reversed by the absence of microglia. Transcriptional analyses of the residual plaque-forming microglia show they exhibit a disease-associated microglia profile. Collectively, we describe the structure, formulation, and efficacy of PLX5622, which allows for sustained microglial depletion and identify roles of microglia in initiating plaque pathogenesis.
Insights
Microglia depletion prevents Alzheimer's disease (AD) plaque formation by inhibiting amyloid-beta deposition. This study highlights microglia's critical role in initiating AD pathogenesis and identifies a potential therapeutic target.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) pathogenesis involves genetic risk factors highly expressed in myeloid cells.
- Microglia, the brain's resident myeloid cells, are crucial for AD development and depend on colony-stimulating factor 1 receptor (CSF1R) signaling for survival.
Purpose of the Study:
- To investigate the role of microglia in initiating Alzheimer's disease (AD) pathology.
- To evaluate the efficacy of a novel brain-penetrant CSF1R inhibitor (PLX5622) for sustained microglial depletion in an AD mouse model.
Main Methods:
- Design and synthesis of PLX5622, a selective and brain-penetrant CSF1R inhibitor.
- Administration of PLX5622 to 5xFAD mice to achieve sustained microglial elimination before and during AD pathology development.
- Analysis of amyloid plaque formation, Aβ deposition, and gene expression in the hippocampus.
Main Results:
- Microglial depletion using PLX5622 prevented parenchymal plaque formation in 5xFAD mice, with Aβ instead depositing in cortical blood vessels (cerebral amyloid angiopathy).
- Absence of microglia reversed altered hippocampal gene expression in 5xFAD mice.
- Residual plaque-forming microglia exhibited a disease-associated microglia profile.
Conclusions:
- Microglia play a critical role in initiating amyloid plaque pathogenesis in Alzheimer's disease.
- Sustained microglial depletion using PLX5622 offers a potential therapeutic strategy for AD by preventing plaque formation.
- Targeting CSF1R signaling in microglia represents a promising avenue for AD treatment.
