Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies.

Title

Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies.

Creator

Casali BT; MacPherson KP; Reed-Geaghan EG; Landreth GE

Publisher

Neurobiology of Disease

Date

2020
2020-05

Description

Alzheimer's disease (AD) is a prominent neurodegenerative disorder characterized by deposition of β-amyloid (Aβ)-containing extracellular plaques, accompanied by a microglial-mediated inflammatory response, that leads to cognitive decline. Microglia perform many disease-modifying functions such as phagocytosis of plaques, plaque compaction, and modulation of inflammation through the secretion of cytokines. Microglia are reliant upon colony-stimulating factor receptor-1 (CSF1R) activation for survival. In AD mouse models, chronic targeted depletion of microglia via CSF1R antagonism attenuates plaque formation in early disease but fails to alter plaque burden in late disease. It is unclear if acute depletion of microglia during the peak period of plaque deposition will alter disease pathogenesis, and if so, whether these effects are reversible upon microglial repopulation. To test this, we administered the CSF1R antagonist PLX5622 to the 5XFAD mouse model of AD at four months of age for approximately one month. In a subset of mice, the drug treatment was discontinued, and the mice were fed a control diet for an additional month. We evaluated plaque burden and composition, microgliosis, inflammatory marker expression, and neuritic dystrophy. In 5XFAD animals, CSF1R blockade for 28 days depleted microglia across brain regions by over 50%, suppressed microgliosis, and reduced plaque burden. In microglial-depleted AD animals, neuritic dystrophy was enhanced, and increased diffuse-like plaques and fewer compact-like plaques were observed. Removal of PLX5622 elicited microglial repopulation and subsequent plaque remodeling, resulting in more compact plaques predominating microglia-repopulated regions. We found that microglia limit diffuse plaques by maintaining compact-like plaque properties, thereby blocking the progression of neuritic dystrophy. Microglial repopulation reverses these effects. Collectively, we show that microglia are neuroprotective through maintenance of plaque compaction and morphologies during peak disease progression.

Subject

Microglia; Inflammation; Neuroprotection; AD; Barrier; CSF1R; Plaques

Rights

Article information provided for research and reference use only. All rights are retained by the journal listed under publisher and/or the creator(s).

Format

journalArticle

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Pages

104956

Volume

142

NEOMED College

NEOMED College of Pharmacy

NEOMED Department

Department of Pharmaceutical Sciences

Update Year & Number

July 2020 List

Citation

Casali BT; MacPherson KP; Reed-Geaghan EG; Landreth GE, “Microglia depletion rapidly and reversibly alters amyloid pathology by modification of plaque compaction and morphologies.,” NEOMED Bibliography Database, accessed July 30, 2021, https://neomed.omeka.net/items/show/11146.

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