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

Microglia limit diffuse plaques by constructing and maintaining dense compact-like plaque properties in AD mouse models and humans, thereby blocking the progression of neuritic dystrophy and reducing tau phosphorylation in the local plaque environment.

“Furthermore, microglia limit diffuse plaques by constructing and maintaining dense compact-like plaque properties in AD mouse models and humans, thereby blocking the progression of neuritic dystrophy and reducing tau phosphorylation in the local plaque environment [12, 38, 106].”

Pharmacological depletion of microglia in ten-month-old 5xFAD mice reduced the plaque burden, and the remaining plaques exhibited increased diffuse-like plaques and fewer compact-like shapes, together with increased dystrophic neuritis.

“Casali et al. showed that pharmacological depletion of microglia in ten-month-old 5xFAD mice reduced the plaque burden, and the remaining plaques exhibited increased diffuse-like plaques and fewer compact-like shapes, together with increased dystrophic neuritis [12].”

Microglia form stable, protective barriers around Aβ plaques and compact Aβ into tightly packed, less toxic forms.

“Microglia are deployed to form stable, protective barriers around Aβ plaques in the AD brain, and work to compact Aβ into tightly packed, less toxic forms (Casali et al., 2020; Condello et al., 2015; Zhao et al., 2017).”

Microglia can use their highly dynamic and mobile processes to compact Aβ fibrils into tightly packed aggregates, reducing Aβ aggregate surface area and limiting their potential neurotoxic effects on nearby neurons.

“They can also use their highly dynamic and mobile processes to compact Aβ fibrils into tightly packed aggregates, reducing Aβ aggregate surface area and thereby limiting their potential neurotoxic effects on nearby neurons (Casali et al., 2020; Condello et al., 2015; Zhao et al., 2017).”

Microglial depletion has been shown to reduce plaque burden but also alter the morphology of plaques.

“With regards to amyloid-β, microglial depletion has been shown to reduce plaque burden but also alter the morphology of plaques (Casali et al., 2020).”

Previous reports suggest that plaque morphology, rather than total amyloid burden, may be a key factor in neurotoxicity and disease progression.

“These findings align with previous reports suggesting that plaque morphology, rather than total amyloid burden, may be a key factor in neurotoxicity and disease progression and suggest that this could be an important role for plaque‐associated PLCγ2 expressing microglia (Casali et al. 2020; Shi et al. 2017; Yuan et al. 2016).”

The degree of plaque compaction positively correlates with neuronal health.

“These protective functions of microglia have been shown to limit axonal dystrophy to neurons in the immediate area, with the degree of plaque compaction positively correlating with neuronal health (Casali et al., 2020; Condello et al., 2015; Zhao et al., 2017).”