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The role of senescence in neurodegenerative diseases

Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process.

To investigate this, we first conducted single-nuclei and single-cell RNA-seqin the hippocampus from young and aged mice. We observed an age-dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16Ink4a-positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. 

Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions’ being a potential therapeutic avenue for alleviating age-associated cognitive impairment.


 Mikolai Ogrodnik, et. al., Whole‐body senescent cell clearance alleviates age‐related brain inflammation and cognitive impairment in mice, Aging Cell, Vol. 20, Issue 2, February 2020
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Link: https://doi.org/10.1111/acel.13296

Inhibition of mTOR Signaling in Parkinson’s Disease Prevents l-DOPA–Induced Dyskinesia

  1. Emanuela Santini1, Myriam Heiman Paul Greengard, Emmanuel Valjent, and Gilberto Fisone. Science Signaling  21 Jul 2009: Vol. 2, Issue 80, pp. ra36

Abstract

Parkinson’s disease (PD), a disorder caused by degeneration of the dopaminergic input to the basal ganglia, is commonly treated with L-DOPA. Use of this drug, however, is severely limited by motor side effects, or dyskinesia. We show that administration of L-DOPA in a mouse model of Parkinsonism led to dopamine D1 receptor–mediated activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which is implicated in several forms of synaptic plasticity. This response occurred selectively in the GABAergic medium spiny neurons that project directly from the striatum to the output structures of the basal ganglia. The L-DOPA–mediated activation of mTORC1 persisted in mice that developed dyskinesia. Moreover, the mTORC1 inhibitor rapamycin prevented the development of dyskinesia without affecting the therapeutic efficacy of L-DOPA. Thus, the mTORC1 signaling cascade represents a promising target for the design of anti-Parkinsonian therapies.

https://stke.sciencemag.org/content/sigtrans/2/80/ra36.full.pdf

Whole body senolytics in humans: 
 
 

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