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

Jun 2, 2020Neurobiology of disease

Removing immune brain cells quickly and reversibly changes amyloid plaques by altering their density and shape

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Abstract

In 5XFAD mice, CSF1R blockade for 28 days depleted microglia by over 50% and reduced plaque burden.

Chronic depletion of microglia can suppress plaque formation in early Alzheimer's disease but may not impact late-stage plaque burden.
Acute microglial depletion during peak plaque deposition alters the composition of plaques, resulting in more diffuse-like plaques and fewer compact-like plaques.
Neuritic dystrophy is enhanced in microglial-depleted Alzheimer's animals, indicating a potential link between microglial presence and neuronal health.
Microglial repopulation after CSF1R blockade leads to plaque remodeling, favoring the formation of more compact plaques in repopulated areas.
Microglia appear to play a protective role by maintaining plaque compaction and morphology, potentially limiting disease progression.

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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.

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

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