Researchers right here present that concentrating on microglia in a mouse mannequin of Alzheimer’s illness to suppress p16 expression can scale back amyloid-β plaques. This seems to be a option to intervene in a maladaptive response to amyloid-β on the a part of microglia, innate immune cells accountable for clearing molecular particles from mind tissue. P16 is a marker of mobile senescence, although may be attribute of non-senescent however nonetheless problematic, pro-inflammatory microglia. There’s a good quantity of proof to recommend that each senescent and overly energetic microglia are essential to the development of neurodegenerative situations similar to Alzheimer’s illness. Senescent cells may be cleared by senolytic therapies, and proof in animal research means that this could assist Alzheimer’s sufferers. Coping with non-senescent, activated and problematic microglia would require a unique technique, nonetheless.
Age-dependent accumulation of amyloid plaques in sufferers with sporadic Alzheimer’s illness (AD) is related to decreased amyloid clearance. Older microglia have a decreased skill to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could possibly be regulated to forestall amyloid accumulation. Moreover, contemplating the aging-related disruption of cell cycle equipment in outdated microglia, we hypothesize that regulating their cell cycle might rejuvenate them and improve their skill to advertise extra environment friendly amyloid clearance.
First, we used gene ontology evaluation of microglia from younger and outdated mice to establish differential expression of cyclin-dependent kinase inhibitor 2A (p16ink4a), a cell cycle issue associated to growing older. We discovered that p16ink4a expression was elevated in microglia close to amyloid plaques in mind tissue from sufferers with AD and 5XFAD mice, a mannequin of AD. Within the BV2 microglia cell line, small interfering RNA (siRNA)-mediated p16ink4a downregulation remodeled microglia with enhanced amyloid phagocytic capability by way of regulated the cell cycle and elevated cell proliferation.
To control microglial phagocytosis by gene transduction, we used poly (D,L-lactic-co-glycolic acid) (PLGA) nanoparticles, which predominantly goal microglia, to ship the siRNA and to manage microglial reactivity. Nanoparticle-based supply of p16ink4a siRNA decreased amyloid plaque formation and the variety of aged microglia surrounding the plaque and reversed studying deterioration and spatial reminiscence deficits. We suggest that downregulation of p16ink4a in microglia is a promising technique for the remedy of Alzheimer’s illness.
Hyperlink: https://doi.org/10.1186/s13024-024-00715-x
