Cellular Senescence in Neurodegenerative Diseases

Abstract

Cellular senescence is a homeostatic biological process characterized by a permanent state of cell cycle arrest that can contribute to the decline of the regenerative potential and function of tissues. The increased presence of senescent cells in different neurodegenerative diseases suggests the contribution of senescence in the pathophysiology of these disorders. Although several factors can induce senescence, DNA damage, oxidative stress, neuroinflammation, and altered proteostasis have been shown to play a role in its onset. Oxidative stress contributes to accelerated aging and cognitive dysfunction stages affecting neurogenesis, neuronal differentiation, connectivity, and survival. During later life stages, it is implicated in the progression of cognitive decline, synapse loss, and neuronal degeneration. Also, neuroinflammation exacerbates oxidative stress, synaptic dysfunction, and neuronal death through the harmful effects of pro-inflammatory cytokines on cell proliferation and maturation. Both oxidative stress and neuroinflammation can induce DNA damage and alterations in DNA repair that, in turn, can exacerbate them. Another important feature associated with senescence is altered proteostasis. Because of the disruption in the function and balance of the proteome, senescence can modify the proper synthesis, folding, quality control, and degradation rate of proteins producing, in some diseases, misfolded proteins or aggregation of abnormal proteins. There is an extensive body of literature that associates cellular senescence with several neurodegenerative disorders including Alzheimer's disease (AD), Down syndrome (DS), and Parkinson's disease (PD). This review summarizes the evidence of the shared neuropathological events in these neurodegenerative diseases and the implication of cellular senescence in their onset or aggravation. Understanding the role that cellular senescence plays in them could help to develop new therapeutic strategies.

Antioxidants in Down Syndrome: From Preclinical Studies to Clinical Trials

“…Finally, there is also evidence that suggests that in fetal and adult DS cells, an increase in OS produces an accumulation of DNA damage and defects in DNA repair mechanisms [63][64][65] that leads to genomic instability. In neurons, these alterations play a central role in the degenerative process associated with oxidative damage in DS and other neurodegenerative diseases [66].…”

“…In addition, both OS and mitochondrial dysfunction induce premature cell senescence [66][67][68], a process that is characterized by a permanent arrest of cell proliferation [69]. Amniocytes and placentas from trisomy 21 pregnancies present a higher prevalence of senescent cells [70].…”

Signalling Pathways Implicated in Alzheimer′s Disease Neurodegeneration in Individuals with and without Down Syndrome

“…AD is characterized by altered proteostasis since many of its pathological characteristics are due to changes in the balance and function of different proteins and peptides [15]. In particular, the accumulation of Aβ in plaques is produced by alterations in the synthesis, folding, and clearance of these peptides.…”

“…Cellular senescence, a homeostatic process which reduces proliferation and helps to prevent the propagation of damaged cells [257,258], is implicated in the neurodegenerative processes found in AD in individuals with or without DS [15].…”

Plasma Tau Variants Detected by a Novel Anti-Tau Monoclonal Antibody: A Potential Biomarker for Alzheimer’s Disease

“…AD is the main cause of dementia in the elderly (accounts for a 60-70% of cases) [4], thus affecting not only the patient, but also their caregivers. Consequently, considering the accelerated aging rate worldwide [5], this disease has turned in recent years in a serious public health issue.…”