This open access review paper covers the high points of what is presently known of the contribution of senescent cells to neurodegenerative conditions. Somatic cells become senescent throughout life, largely as they reach the Hayflick limit to replication, but also due to damage or a toxic local environment. Senescent cells halt replication and begin to secrete pro-inflammatory signals to attract the immune system. In youth, senescent cells are rapidly cleared by programmed cell death or by immune cells. With age, the immune system becomes less efficient. As a consequence senescent cells begin to accumulate, and they help to generate a state of chronic inflammation and tissue dysfunction, contributing to the onset and progression of age-related disease.
Cellular senescence is a ubiquitous process and is a state of irreversible cell cycle arrest, induced by a variety of cellular stimuli such as DNA damage, telomere shortening/dysfunction, oncogenic activation and chromatin disruption. Cellular senescence limits the replicative lifespan of cells and contributes to aging and age-related diseases. Senescent cells resist apoptosis and secrete persistent pro-inflammatory signals that are fatal to neighboring cells.
Neurodegenerative disease are characterized by chronic, progressive and pathological changes in the brain, such as neuronal death, abnormal aggregation of proteins and inflammation. Recent evidences suggest that the pathological changes in the neurodegenerative disease begins much ahead of the actual appearance of the symptoms. Prolonged exposure to stress such as DNA damage may induce cellular senescence and contribute to the pathogenesis of the disease by altering metabolism and affecting gene expression.
Alzheimer's disease accumulates toxic protein aggregates in the brain, including amyloid-beta plaques and tau tangles. Recent studies have shown that cellular senescence plays a role in developing and accumulating these toxic protein aggregates. As evidenced by increased SA-β-gal expression, p53 expression, a mediator of cellular senescence, an increase in the release of senescence-associated secretory phenotype (SASP) components, DNA damage, telomere attrition or damage, and senescence-like morphological changes, increased senescence is found in various cell types of Alzheimer's disease brains, including astrocytes, microglia, and neurons. In 2018 researchers found that cellular senescence is associated with tau protein aggregation in the brain. The researchers combined genomic analysis with pharmacological interventions to induce senescence in neurons, which led to increased tau aggregation and neuronal dysfunction. Conversely, clearance of senescent cells reduced tau-dependent pathology.
Parkinson's disease (PD) is the most common movement disorder and the second most prevalent neurodegenerative disease after Alzheimer's disease. Pre-symptomatic midbrain inflammation plays a crucial role in the pathology of PD. Cellular senescence triggers a pro-inflammatory response, the SASP, so senescence and SASP together are a strong contributing factor in the pathophysiology of PD. The dopaminergic (DA) neurons in PD has been noted to express various senescence markers. Neuronal senescence has also been recognized to contribute to the "inflammaging" seen in PD. In a recent study, it was found that α-synuclein (α-syn) aggregates triggers stress induced premature senescence in PD models. α-syn preformed fibrils triggers cellular senescence in astrocytes and microglia and leads to their activation. Overactivation of microglia has been detected in PD patients. Microglia when activated produce inflammatory products which might contribute to the dopaminergic neuronal death in PD patients.
Link: https://doi.org/10.3...gi.2023.1292053
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