USP16 Inhibition May Produce Benefits in an Alzheimer's Mouse Model by Lowering the Burden of Cellular Senescence

Previous studies have shown benefits in some mouse models of Alzheimer's disease (not the one chosen here) via clearance of senescent cells. These cells produce chronic inflammation, and that inflammation is thought to be influential in driving the pathology of Alzheimer's disease. One caveat is that these models are highly artificial, but nonetheless, there is good evidence for the human condition to involve cellular senescence and otherwise inflammatory behavior in the supporting cells of the brain.

Researchers here note that USP16 inhibition improves function in an Alzheimer's mouse model; this acts to downregulate Cdkn2a, one of the gene loci involved in the onset of cellular senescence. The results here are supportive of a role for cellular senescence in neurodegeneration, but suppression of the onset of cellular senescence may or may not be the best approach. Where inflammation is driving undamaged cells into senescence, then it could be beneficial. But there is always the risk of suppressing senescence for cells that really should become senescent, to protect against potentially cancerous damage. Where the balance of benefit and risk falls can only really be determined by experiment.

Alzheimer's disease (AD) is a progressive neurodegenerative disease observed with aging that represents the most common form of dementia. To date, therapies targeting end-stage disease plaques, tangles, or inflammation have limited efficacy. Therefore, we set out to identify a potential earlier targetable phenotype. Utilizing a mouse model of AD and human fetal cells harboring mutant amyloid precursor protein, we show cell intrinsic neural precursor cell (NPC) dysfunction precedes widespread inflammation and amyloid plaque pathology, making it the earliest defect in the evolution of the disease.

We demonstrate that reversing impaired NPC self-renewal via genetic reduction of USP16, a histone modifier and critical physiological antagonist of the Polycomb Repressor Complex 1, can prevent downstream cognitive defects and decrease astrogliosis in vivo. Reduction of USP16 led to decreased expression of senescence gene Cdkn2a and mitigated aberrant regulation of the Bone Morphogenetic Signaling (BMP) pathway, a previously unknown function of USP16. Thus, we reveal USP16 as a novel target in an AD model that can both ameliorate the NPC defect and rescue memory and learning through its regulation of both Cdkn2a and BMP signaling.


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