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Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress.

ABSTRACT: When an individual is under stress, the undesired effect on the brain often exceeds expectations. Additionally, when stress persists for a long time, it can trigger serious health problems, particularly depression. Recent studies have revealed that depressed patients have a higher rate of brain aging than healthy subjects and that depression increases dementia risk later in life. However, it remains unknown which factors are involved in brain aging triggered by chronic stress. The most critical change during brain aging is the decline in cognitive function. In addition, cellular senescence is a stable state of cell cycle arrest that occurs because of damage and/or stress and is considered a sign of aging. We used the chronic unpredictable stress (CUS) model to mimic stressful life situations and found that, compared with nonstressed control mice, CUS-treated C57BL/6 mice exhibited depression-like behaviors and cognitive decline. Additionally, the protein expression of the senescence marker p16^INK4a was increased in the hippocampus, and senescence-associated β-galactosidase (SA-β-gal)-positive cells were found in the hippocampal dentate gyrus (DG) in CUS-treated mice. Furthermore, the levels of SA-β-gal or p16^INK4a were strongly correlated with the severity of memory impairment in CUS-treated mice, whereas clearing senescent cells using the pharmacological senolytic cocktail dasatinib plus quercetin (D + Q) alleviated CUS-induced cognitive deficits, suggesting that targeting senescent cells may be a promising candidate approach to study chronic stress-induced cognitive decline. Our findings open new avenues for stress-related research and provide new insight into the association of chronic stress-induced cellular senescence with cognitive deficits.

SUBMITTER: Lin YF

PROVIDER: S-EPMC8163993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimsDepression is one of the leading causes of disability worldwide. The receptor for advanced glycosylation end products (RAGE) is closely related to chronic stress and is a target of F-box protein O10 (FBXO10) which promotes the degradation of RAGE by ubiquitination. Here, we explored the role of FBXO10 and RAGE in chronic unpredictable stress (CUS)-induced behavioral despair, cognitive impairment, neuroinflammation, and the polarization microglia.MethodsMale C57BL/6 mice with or without infusion of viral in the medial prefrontal cortex (PFC) were subjected to CUS. Then the mice were exposed to forced swim test, sucrose consumption test, novelty-suppressed feeding test, and temporal object recognition task to assess the behavioral despair and cognitive impairment. Inflammatory cytokines and the neurotrophic factor brain-derived neurotrophic factor (BDNF) levels in PFC were assessed by enzyme-linked immunosorbent assay. Immunofluorescence and immunohistochemistry staining were performed to observe the activation and phenotypic transformation of microglia in PFC. LPS-induced cell model was constructed to explore the effect of FBXO10/RAGE axis in the polarization of microglia in vitro.ResultsFBXO10 promoted RAGE degradation by ubiquitination in BV2 cells. FBXO10 protein levels were reduced whereas RAGE protein levels were enhanced in CUS mice. FBXO10 overexpression or RAGE knockdown inhibited proinflammatory cytokine release, promoted BDNF expression, mitigated the depressive-like and cognitive impairment behaviors, and affected the polarization of microglia induced by CUS exposure. FBXO10/RAGE axis promoted the polarization of microglia from the M1 to the M2 phenotype in vitro. Moreover, p38 MAPK and NF-κΒ were identified to be the downstream effect factors for FBXO10/RAGE axis.ConclusionsFBXO10 administration prevents CUS-induced behavioral despair, cognitive impairment, neuroinflammation, and the polarization of microglia through decreasing the accumulation of RAGE, p38 MAPK, and NF-κΒ, suggesting potential therapeutic strategies for the prevention and treatment of depression.

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Cellular senescence as a driver of cognitive decline triggered by chronic unpredictable stress.

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