Cellular senescence in Alzheimer's disease: from physiology to pathology

Abstract

Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, characterized by the accumulation of Aβ and abnormal tau hyperphosphorylation. Despite substantial efforts in development of drugs targeting Aβ and tau pathologies, effective therapeutic strategies for AD remain elusive. Recent attention has been paid to the significant role of cellular senescence in AD progression. Mounting evidence suggests that interventions targeting cellular senescence hold promise in improving cognitive function and ameliorating hallmark pathologies in AD. This narrative review provides a comprehensive summary and discussion of the physiological roles, characteristics, biomarkers, and commonly employed in vivo and in vitro models of cellular senescence, with a particular focus on various cell types in the brain, including astrocytes, microglia, oligodendrocyte precursor cells, neurons, and endothelial cells. The review further delves into factors influencing cellular senescence in AD and emphasizes the significance of targeting cellular senescence as a promising approach for AD treatment, which includes the utilization of senolytics and senomorphics.

Keywords: Alzheimer’s disease; Cellular senescence; Senolytics; Senomorphics.

Fig. 1

Pathological vicious cycle of cellular senescence in AD. Under pathological conditions of AD, cellular senescence induces SASP, leading to accumulation of senescent cells. This process is accompanied by excessive release of reactive oxygen species and pro-inflammatory factors, exacerbating mitochondrial dysfunction, oxidative stress, and inflammatory responses. Moreover, it accelerates Aβ deposition and excessive phosphorylation of tau, forming a vicious cycle between cellular senescence and AD pathology. SASP, senescence-associated secretory phenotype

Fig. 2

Summary of cellular senescence in AD. Cellular senescence, including stress-induced senescence and replicative senescence in the brain, is induced by multiple factors. Moreover, the factors inducing cellular senescence affect various cell types in AD, including astrocytes, microglia, oligodendrocyte precursor cells (OPCs), neurons, and endothelial cells. The senescent cells further exacerbate AD pathology. Senotherapeutics, which include senolytics and senomorphics, are strategies to alleviate cellular senescence. Senolytics promote the apoptosis of senescent cells, clearing them from the system, while senomorphics mitigate the SASP (senescence-associated secretory phenotype), thereby attenuating cellular senescence. Clearing cellular senescence holds promise for alleviating AD pathology