Researchers here show that targeting microglia in a mouse model of Alzheimer's disease to suppress p16 expression can reduce amyloid-β plaques. This appears to be a way to interfere in a maladaptive reaction to amyloid-β on the part of microglia, innate immune cells responsible for clearing molecular debris from brain tissue. P16 is a marker of cellular senescence, though may also be characteristic of non-senescent but still problematic, pro-inflammatory microglia. There is a good amount of evidence to suggest that both senescent and overly active microglia are important to the progression of neurodegenerative conditions such as Alzheimer's disease. Senescent cells can be cleared by senolytic therapies, and evidence in animal studies suggests that this should help Alzheimer's patients. Dealing with non-senescent, activated and problematic microglia will require a different strategy, however.
Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer's disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia, we hypothesize that regulating their cell cycle could rejuvenate them and enhance their ability to promote more efficient amyloid clearance.
First, we used gene ontology analysis of microglia from young and old mice to identify differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle factor related to aging. We found that p16ink4a expression was increased in microglia near amyloid plaques in brain tissue from patients with AD and 5XFAD mice, a model of AD. In the BV2 microglia cell line, small interfering RNA (siRNA)-mediated p16ink4a downregulation transformed microglia with enhanced amyloid phagocytic capacity through regulated the cell cycle and increased cell proliferation.
To regulate microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly target microglia, to deliver the siRNA and to control microglial reactivity. Nanoparticle-based delivery of p16ink4a siRNA reduced amyloid plaque formation and the number of aged microglia surrounding the plaque and reversed learning deterioration and spatial memory deficits. We propose that downregulation of p16ink4a in microglia is a promising strategy for the treatment of Alzheimer's disease.
Link: https://doi.org/10.1...024-024-00715-x
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