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

Lin, Yu Fen; Wang, Li Yun; Chen, Chi Sheng; Li, Chia Chun; Hsiao, Ya Hsin

doi:10.1016/j.ynstr.2021.100341

Cited by 25 publications

(23 citation statements)

References 98 publications

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“…We found that CUS significantly reduced sucrose preference and increased the immobility time. These results were consistent with those of previous studies, indicating that the CUS-induced depression model was successfully established (Lin et al, 2021).…”

Section: Discussionsupporting

confidence: 93%

Microglia Loss and Astrocyte Activation Cause Dynamic Changes in Hippocampal [18F]DPA-714 Uptake in Mouse Models of Depression

Guo

Qiu

Wang

et al. 2022

Front. Cell. Neurosci.

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Major depression is a serious and chronic mental illness. However, its etiology is poorly understood. Although glial cells have been increasingly implicated in the pathogenesis of depression, the specific role of microglia and astrocytes in stress-induced depression remains unclear. Translocator protein (TSPO) has long been considered a marker of neuroinflammation and microglial activation. However, this protein is also present on astrocytes. Thus, it is necessary to explore the relationships between TSPO, microglia, and astrocytes in the context of depression. In this study, C57BL/6J male mice were subjected to chronic unpredictable stress (CUS) for 5 weeks. Subsequently, sucrose preference and tail suspension tests (TSTs) were performed to assess anhedonia and despair in these mice. [18F]DPA-714 positron emission tomography (PET) was adopted to dynamically assess the changes in glial cells before and 2, 4, or 5 weeks after CUS exposure. The numbers of TSPO+ cells, ionized calcium-binding adaptor molecule (Iba)-1+ microglial cells, TSPO+/Iba-1+ cells, glial fibrillary acidic protein (GFAP)+ astrocytes, TSPO+/GFAP+ cells, and TUNEL-stained microglia were quantified using immunofluorescence staining. Real-time PCR was used to evaluate interleukin (IL)-1β, IL-4, and IL-18 expression in the hippocampus. We observed that hippocampal [18F]DPA-714 uptake significantly increased after 2 weeks of CUS. However, the signal significantly decreased after 5 weeks of CUS. CUS significantly reduced the number of Iba-1+, TSPO+, and TSPO+/Iba-1+ cells in the hippocampus, especially in the CA1 and dentate gyrus (DG) subregions. However, this intervention increased the number of GFAP+ astrocytes in the CA2/CA3 subregions of the hippocampus. In addition, microglial apoptosis in the early stage of CUS appeared to be involved in microglia loss. Further, the expression of pro-inflammatory cytokines (IL-1β and IL-18) was significantly decreased after CUS. In contrast, the expression of the anti-inflammatory cytokine IL-4 was significantly increased after 2 weeks of CUS. These results suggested that the CUS-induced dynamic changes in hippocampal [18F]DPA-714 uptake and several cytokines may be due to combined microglial and astrocyte action. These findings provide a theoretical reference for the future clinical applications of TSPO PET.

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Section: Discussionsupporting

confidence: 93%

Microglia Loss and Astrocyte Activation Cause Dynamic Changes in Hippocampal [18F]DPA-714 Uptake in Mouse Models of Depression

Guo

Qiu

Wang

et al. 2022

Front. Cell. Neurosci.

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“…Rodent studies have demonstrated senescent cell accumulation in the brain in response to accumulation of tau ( 90 , 97 ) or Aβ protein ( 98 ); dysfunctional immune system ( 96 ); high-fat diet or obesity ( 99 ); insulin resistance ( 100 ); chronic unpredictable stress ( 101 ); environmental neurotoxins ( 102 ); and brain injury ( 103 ). Studies using postmortem human brain tissue have identified multiple senescent cell types in AD, including astrocytes ( 104 ), neurons ( 90 , 105 ), microglia ( 106 ), oligodendrocyte precursor cells ( 98 ), and endothelial cells ( 107 ).…”

Section: Biological Aging Hallmarks Of Cognitive Decline and Adrdmentioning

confidence: 99%

Biological aging processes underlying cognitive decline and neurodegenerative disease

Gonzales

Garbarino

Pollet

et al. 2022

Journal of Clinical Investigation

119

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Alzheimer’s disease and related dementias (ADRD) are among the top contributors to disability and mortality in later life. As with many chronic conditions, aging is the single most influential factor in the development of ADRD. Even among older adults who remain free of dementia throughout their lives, cognitive decline and neurodegenerative changes are appreciable with advancing age, suggesting shared pathophysiological mechanisms. In this Review, we provide an overview of changes in cognition, brain morphology, and neuropathological protein accumulation across the lifespan in humans, with complementary and mechanistic evidence from animal models. Next, we highlight selected aging processes that are differentially regulated in neurodegenerative disease, including aberrant autophagy, mitochondrial dysfunction, cellular senescence, epigenetic changes, cerebrovascular dysfunction, inflammation, and lipid dysregulation. We summarize research across clinical and translational studies to link biological aging processes to underlying ADRD pathogenesis. Targeting fundamental processes underlying biological aging may represent a yet relatively unexplored avenue to attenuate both age-related cognitive decline and ADRD. Collaboration across the fields of geroscience and neuroscience, coupled with the development of new translational animal models that more closely align with human disease processes, is necessary to advance novel therapeutic discovery in this realm.

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“…By measuring this SASP index, Diniz and colleagues found that the interaction of depression and somatic health variables, in particular obesity, was associated with greater cellular senescence in young and middle-aged adults ( 128 ). Together with animal studies that link obesity to increased senescence and depression and anxiety-like phenotypes ( 108 , 129 ), these data suggest senescence as a potential key contributor in the interaction of depression, obesity, and inflammation.…”

Section: Adipose Tissue Compartments Inflammation and Depressionmentioning

confidence: 66%

Adipose Tissue Compartments, Inflammation, and Cardiovascular Risk in the Context of Depression

et al. 2022

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The neurobiological and behavioral underpinnings linking mental disorders, in particular, major depressive disorder (MDD), with cardiovascular disorders are a matter of debate. Recent research focuses on visceral (intra-abdominal and epicardial) adipose tissue and inflammation and their impact on the development of cardiometabolic disorders. Intra-abdominal adipose tissue is defined as an endocrine active fat compartment surrounding inner organs and is associated with type 2 diabetes mellitus, a risk factor for the later development of cardiovascular disorders. Epicardial (pericardial) adipose tissue is a fat compartment surrounding the heart with close proximity to the arteries supporting the heart. Visceral adipose tissue (VAT) is an important source of inflammatory mediators that, in concert with other risk factors, plays a leading role in cardiovascular diseases. In conjunction with the behavioral (physical inactivity, sedentary lifestyle), psychological (adherence problems), and hormonal (dysfunction of the hypothalamus–pituitary–adrenal axis with subsequent hypercortisolism) alterations frequently accompanying MDD, an enhanced risk for cardiovascular disorders results.

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

Cited by 25 publications

References 98 publications

Microglia Loss and Astrocyte Activation Cause Dynamic Changes in Hippocampal [18F]DPA-714 Uptake in Mouse Models of Depression

Microglia Loss and Astrocyte Activation Cause Dynamic Changes in Hippocampal [18F]DPA-714 Uptake in Mouse Models of Depression

Biological aging processes underlying cognitive decline and neurodegenerative disease

Adipose Tissue Compartments, Inflammation, and Cardiovascular Risk in the Context of Depression

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