The role of cellular senescence in neurodegenerative diseases

Abstract

Increasing evidence has revealed that cellular senescence drives NDs, including Alzheimer's disease (AD) and Parkinson's disease. Different senescent cell populations secrete senescence-associated secretory phenotypes (SASP), including matrix metalloproteinase-3, interleukin (IL)-1α, IL-6, and IL-8, which can harm adjacent microglia. Moreover, these cells possess high expression levels of senescence hallmarks (p16 and p21) and elevated senescence-associated β-galactosidase activity in in vitro and in vivo ND models. These senescence phenotypes contribute to the deposition of β-amyloid and tau-protein tangles. Selective clearance of senescent cells and SASP regulation by inhibiting p38/mitogen-activated protein kinase and nuclear factor kappa B signaling attenuate β-amyloid load and prevent tau-protein tangle deposition, thereby improving cognitive performance in AD mouse models. In addition, telomere shortening, a cellular senescence biomarker, is associated with increased ND risks. Telomere dysfunction causes cellular senescence, stimulating IL-6, tumor necrosis factor-α, and IL-1β secretions. The forced expression of telomerase activators prevents cellular senescence, yielding considerable neuroprotective effects. This review elucidates the mechanism of cellular senescence in ND pathogenesis, suggesting strategies to eliminate or restore senescent cells to a normal phenotype for treating such diseases.

Keywords: Alzheimer’s disease; Amyloid β · tau protein; Cellular senescence; Neurodegenerative diseases; Telomere shortening.

Fig. 1

Brain-cell senescence contributes to neurodegeneration. Senescent astrocytes reveal dysfunctional mitochondria, elevating reactive oxygen species (ROS) levels to activate the nuclear factor kappa B (NF-κB) pathway and promote interleukin (IL)-6 and interferon-γ (IFNγ) secretions. This results in beta-amyloid (Aβ) accumulation and tau hyperphosphorylation, leading to neurofibrillary tangle formation. Furthermore, senescent astrocytes increase glutamate release and stimulate oligodendrocyte senescence, manifested as increased expression of the senescence markers, senescence-associated β-galactosidase (SA-β-gal), and p21. Oligodendrocyte senescence is responsible for myelin damage and contributes to neurodegeneration. Senescent astrocytes and oligodendrocytes secrete a sufficient SASP, which is detrimental to adjacent microglia. Senescent disease-associated microglia express elevated levels of SA-β-gal, p16, and p21, secrete SASP components, and contribute to Aβ pathology

Fig. 2

The role of cellular senescence in forming Aβ and tau proteins. A In the Alzheimer’s disease (AD) mouse model, senescent brain cells express elevated SA-β-gal, p16, and p21 levels. These phenotypes contribute to Aβ pathology, and Aβ plaques induce oligodendrocyte progenitor cellular senescence by increasing reactive oxygen species (ROS) production, resulting in the activation of the deoxyribonucleic acid (DNA) damage response (DDR) and p16 and p21 upregulation. B P16-positive senescent astrocytes and microglia accumulate in tau-dependent neurodegenerative diseases. Tau oligomers trigger cellular senescence by releasing SASP and HMGB1. C Selective clearance of senescent cells from AD mice attenuates Aβ load and prevents the deposition of tau-protein tangles, thereby improving cognitive deficits

Fig. 3

Telomere damage-induced senescence promotes neurodegenerative diseases. DNA damage leads to the gradual shortening of telomeres, one or a few DNA damage response (DDR) signaling telomeres, the ends of chromosomes, and signals finally converge on p53 and p16 activation, causing cell cycle arrest. Eventually, sustained DDR activation induces cellular senescence. Telomere dysfunction causes cellular senescence, which stimulates IL-6, TNF-α, and IL-1β secretions. The intertwined process of senescence and inflammation is correlated with cognitive decline and leads to neurodegenerative diseases. Telomerase comprises telomerase reverse transcriptase (TERT) and telomerase ribonucleic acid components (TERC). Forced expression of telomerase activators prevents cellular senescence, showing substantial neuroprotective effects, which rescues degenerative diseases with critically shortened telomeres

Fig. 4

Cellular senescence drives neurodegenerative diseases. DNA damage accumulates at the telomere, where telomere shortening activates the DNA damage response (DDR), triggering cellular senescence and generating senescence-associated heterochromatin foci. DNA damage is related to the apical kinases, ATM and ATR, and the downstream kinases, CHK2 and CHK1. Subsequently, signals converge upon p53 activation, which causes cell cycle arrest and governs p21 and p16 expression. Prolonged DDR activation triggers senescence. Pro-inflammatory IL-8 and IL-6, mediated in an IL-1-dependent manner, induce SASP genes by enhancing NF-κB activity, regulating SASP drives inflammation and SA-β-gal. Accumulated inflammatory cytokines and SA-β-gal aggravate Aβ fibers, tau protein, and α-synuclein, promote Aβ deposition and NFT formation, finally inducing neurodegenerative disease