Microglial autophagy-mediated clearance of amyloid-beta plaques is dysfunctional in Alzheimer’s Disease mice
The Journal of Immunology(2021)
Abstract
Abstract Alzheimer’s Disease (AD) is a neurodegenerative disorder with no preventative methods or cure. Deposition of aggregated amyloid-beta (Aβ) in the brain is hypothesized to initiate a vicious cascade, leading to inflammation and tissue damage. Microglia are brain-resident immune cells which help maintain homeostasis and clear protein aggregates, including Aβ. However, in AD, microglia produce inflammatory mediators and do not adequately clear Aβ. This project seeks to determine how healthy microglia clear Aβ from the brain and why diseased AD microglia do not. Autophagy is a homeostatic process providing the cell with energy during stress. Autophagy can act as a defense mechanism, by clearing foreign particles and defective proteins. Previous research on AD established that autophagy is dysfunctional in neurons, but autophagy is not well-characterized in AD microglia. Functional autophagy requires expression of multiple autophagy proteins. We hypothesized that AD microglia fail to clear Aβ due to reduced expression of autophagy proteins and that restoring expression of these proteins will enhance autophagy activity. Utilizing microglia from adult AD model mice and various autophagy mice, we demonstrated that AD microglia do not degrade Aβ due to reduced expression of autophagy proteins, which are necessary for Aβ degradation. We identified an upregulated cluster of microRNA in microglia from mouse and human AD brain tissue samples. Inhibiting these microRNA improves expression of specific autophagy proteins and restores Aβ degradation in AD mouse microglia. Our findings indicate that autophagy is dysfunctional in AD microglia and establish a mechanism behind dysfunctional autophagy which may be therapeutically targeted.
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Key words
alzheimers,autophagy-mediated,amyloid-beta
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