Cell senescence in neuropathology: A focus on neurodegeneration and tumours

Abstract

Since the initial discovery and description of senescent cells by Hayflick and Moorhead in 1961 [1], the field of senescence has evolved and expanded immensely. Hayflick originally observed that primary human fibroblast cell cultures had a finite proliferative capacity in vitro. This finite proliferative capacity is now termed replicative senescence and is due to the gradual attrition of telomeres over serial passages [2]. It was initially proposed that replicative senescence was the driver of organismal ageing due to the possible lack

Neuroinflammation in Alzheimer’s Disease

“…Their effects are mainly paracrine, but may become systemic as some of the soluble mediators may get into the circulation [ 257 , 258 , 259 ]. Prominent SASP regulators include p38MAPK, NFκB C/EBPβ, GATA4, and mechanistic target of rapamycin (mTOR) [ 260 , 261 , 262 ]. Senescent markers are up-regulated in the astrocytes of AD patients and Aβ elicits senescence in astrocytes in vitro via ROS accompanied by p38, IL-6, and IL-8 up-regulation [ 263 ].…”

Alpha-Synuclein Preformed Fibrils Induce Cellular Senescence in Parkinson’s Disease Models

“…Cellular senescence is considered a potent tumor suppressive mechanism resulting in cell cycle arrest which triggers a pro-inflammatory response known as the senescence-associated secretory phenotype or SASP [ 4 , 5 ]. Since neurons are non-proliferative, they have traditionally not been considered to be capable of undergoing cellular senescence, although excessive extra- or intra-cellular stress can lead to neuronal death as well as cellular senescence [ 5 , 6 ]. Recent publications have suggested that senescence and the SASP may be strong contributing factors to PD pathology [ 4 , 6 , 7 , 8 ].…”

“…Since neurons are non-proliferative, they have traditionally not been considered to be capable of undergoing cellular senescence, although excessive extra- or intra-cellular stress can lead to neuronal death as well as cellular senescence [ 5 , 6 ]. Recent publications have suggested that senescence and the SASP may be strong contributing factors to PD pathology [ 4 , 6 , 7 , 8 ]. However, it is still not well understood what cell-types undergo stress-mediated senescence in the central nervous system (CNS).…”

“…We further examined whether the markers of cellular senescence were associated with human PD pathology in SNpc. We hypothesized that α-syn aggregates trigger stress-induced premature senescence (SIPS) and/or activate astrocytes and microglia [ 5 , 6 , 10 , 15 ]. To address this, the presence of cellular senescence was determined using well-known senescence markers, including Special AT-rich sequence binding protein 1 (SATB1), Lamin B1 and High Mobility Group Box 1 (HMGB1), tumor suppressors p21 and p16, and the endo/lysosomal marker, LAMP1 [ 16 , 17 , 18 , 19 , 20 ], as well as abnormal astrocyte morphology in α-syn PFF-induced PD mouse models [ 8 , 21 , 22 ].…”

“…Our data show that α-syn PFF treatment reduced the levels of SATB1, LaminB1 and HMGB1 and led to an increase in the levels of p21 [ 7 , 20 ]. Since SATB1, HMGB1 and Lamin B1 are chromatin organizer/transcription factor, chromatin protein or nuclear membrane proteins, respectively, the regulation of those proteins would be involved in gene expression, particularly related to cellular senescence [ 5 , 6 ]. Our results strongly suggest that the cellular senescence process plays a role in PD pathology through senescence induction in astrocytes and possibly microglia in brain regions affected in PD [ 8 , 21 , 22 ].…”