Cellular Senescence in Neurodegenerative Diseases
Martínez-Cué C, Rueda N. Cellular Senescence in Neurodegenerative Diseases. Front Cell Neurosci. 2020 Feb 11;14:16. doi: 10.3389/fncel.2020.00016. PMID: 32116562; PMCID: PMC7026683.
Cellular senescence is necessary to prevent the spread of damaged cells and could be a type of cell differentiation. There can be acute or chronic senescence.
Acute senescence is part of normal body functioning and processese like tissue repair.
Chronic senescence is induced by extended exposure to stress and this produces cellular and tissue alterations.
- Replicative senescence Stress induced premature senescence (SIPS)
- Mitochondrial dysfunction-associated senescence
General Senescence phenotypes
Permanent cell cycle arrest because entrance to the S phase
SASP: synthesis and release of proinflammatory cytokines, growth factors
Oxidative stress and mitochondrial dysfunction: high levels of oxidative stress induce senescence during aging and promote neuronal DNA damage, deregulated DNA damage response (DDR), changes to cell cycle progression and cell morphology, premature replicative senescence.
Changes to cellular metabolism from altered mitochondrial function.
Damage and alterations in DNA damage response
Telomere shortening and dysfunction: there is reduced DNA repair and cell cycle arrest. While telomeric shortening is a major aging mechanism, telomere length does not always correlate with senescence
Epigenetic modifications: changes in methylation enzyme activity that are associated with neuropathology
Morphological changes: cytoskeletal rearrangement, more flat and irregular shape
Altered proteostasis: increased unfolded protein response associated with endoplasmic reticulum stress.
Promotion of chronic inflammation: neuroinflammation is both a trigger and a consequence of senescence and can spread the damage to neighbouring cells
reduction in nervous system regenerative capacity because of the cell cycle arrest from senescence
Loss of CNS cell function from the senescence and cell cycle arrests
Senescence in Alzheimer’s Disease
Increased senescence is found in AD brains through SA-β-gal expression, p53 expression, release of SASP components, DNA damage, telomeric damage and senescence-like morphological changes.
Increased oxidative stress, neuroinflammation, and cellular senescence increase Aβ burden, tau hyperphosphorylation, neuronal death and accelerated cognitive decline, all symptoms and pathology in Alzheimer’s disease
The expression of senescence associated genes was shown to be upregulated on exposure to Aβ.
Senescence Phenotypes in AD
Permanent cell cycle arrest: Aβ hypothesis: neurons are induced to divide which causes them to enter senescence
SASP: microglial overactivation, enhanced release of proinflammatory cytokines that aggravate Aβ and tau pathology
Oxidative stress and mitochondrial dysfunction: increased ROS and altered mitochondrial structure and function - leads to cellular changes associated with senescence
Telomeric DNA damage: non-telomeric DNA damage and repair: Increased DNA
Damage and alterations in DNA damage response
Epigenetic modifications: aberrant phosphorylation of histones, changes in methylation of AD critical genes - what genes?
Morphological changes: increased size, flat and irregular shape, changes in membrane composition
Altered proteostasis: loss of protein homeostasis, nuclear dysfunction, accumulation of abnormal proteins (amyloid peptides and hyperphosphorylated tau)