Cellular senescence in neuroinflammatory disease: new therapies for old cells?

Nelke, Christopher; Schroeter, Christina B.; Pawlitzki, Marc; Meuth, Sven G.; Ruck, Tobias

doi:10.1016/j.molmed.2022.07.003

Cited by 23 publications

(13 citation statements)

References 107 publications

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“…Brain aging and related cognitive deficiency have been attributed to diverse molecular processes including chronic inflammation and cellular senescence 42 . This has been studied both in normal murine aging 24 , as well as in different age-related mouse models of neurodegeneration such as Parkinson’s disease 43 , tauopathies 23,44 , amyloid-beta neuropathology 22 , and neuropsychiatric disorders 45 .…”

Section: Discussionmentioning

confidence: 99%

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Aguado

Amarilla

Fard

et al. 2023

Preprint

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Aging is the primary risk factor for most neurodegenerative diseases, and recently coronavirus disease 2019 (COVID-19) has been associated with severe neurological manifestations that can eventually impact neurodegenerative conditions in the long-term. The progressive accumulation of senescent cells in vivo strongly contributes to brain aging and neurodegenerative co-morbidities but the impact of virus-induced senescence in the aetiology of neuropathologies is unknown. Here, we show that senescent cells accumulate in physiologically aged brain organoids of human origin and that senolytic treatment reduces inflammation and cellular senescence; for which we found that combined treatment with the senolytic drugs dasatinib and quercetin rejuvenates transcriptomic human brain aging clocks. We further interrogated brain frontal cortex regions in postmortem patients who succumbed to severe COVID-19 and observed increased accumulation of senescent cells as compared to age-matched control brains from non-COVID-affected individuals. Moreover, we show that exposure of human brain organoids to SARS-CoV-2 evoked cellular senescence, and that spatial transcriptomic sequencing of virus-induced senescent cells identified a unique SARS-CoV-2 variant-specific inflammatory signature that is different from endogenous naturally-emerging senescent cells. Importantly, following SARS-CoV-2 infection of human brain organoids, treatment with senolytics blocked viral retention and prevented the emergence of senescent corticothalamic and GABAergic neurons. Furthermore, we demonstrate in human ACE2 overexpressing mice that senolytic treatment ameliorates COVID-19 brain pathology following infection with SARS-CoV-2. In vivo treatment with senolytics improved SARS-CoV-2 clinical phenotype and survival, alleviated brain senescence and reactive astrogliosis, promoted survival of dopaminergic neurons, and reduced viral and senescence-associated secretory phenotype gene expression in the brain. Collectively, our findings demonstrate SARS-CoV-2 can trigger cellular senescence in the brain, and that senolytic therapy mitigates senescence-driven brain aging and multiple neuropathological sequelae caused by neurotropic viruses, including SARS-CoV-2.

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Section: Discussionmentioning

confidence: 99%

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Aguado

Amarilla

Fard

et al. 2023

Preprint

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“…Senescent cells develop a senescence-associated secretory phenotype (SASP) characterized by a set of proinflammatory cytokines, chemokines, reactive oxygen species, growth factors and proteases, and interact through certain receptors (e.g., intercellular adhesion molecule-1 (ICAM-1)) and insoluble factors (e.g., fibronectin, collagen). SASP leads to immune cell recruitment, particularly via interleukin (IL)-6 and IL-8 secretion, and overall creates a local microenvironment that promotes senescence dissemination, i.e., imparts stress on surrounding cells, and chronic (inflammatory) tissue damage, which in turn drives chronic low-grade neuroinflammation and finally, neurodegeneration [ 76 , 77 ]. Indeed, immunosenescence, e.g., through reduction of mitochondrial energy production in chronically activated astrocytes and microglia has been established in ALS pathophysiology [ 78 , 79 ].…”

Section: Vascular Supply Mediates Brain Vascular Healthmentioning

confidence: 99%

“…Senotherapeutics reduce cellular senescence and may present an innovative strategy to treat incurable diseases. They are currently being tested in several clinical trials for neurodegenerative diseases, mainly AD [ 76 ]. Senotherapeutics either suppress the SASP (senomorphics) or promote death of senescent cells (senolytics).…”

Section: Targeting Brain Vascular Health To Preserve Microvascular In...mentioning

confidence: 99%

“…Senotherapeutics either suppress the SASP (senomorphics) or promote death of senescent cells (senolytics). Senolytic targets include B-cell lymphoma 2 protein family members (Bcl-2), the phosphatidylinositol 3-kinase-related kinase family (PI3K), heat shock protein 90 (Hsp90), the cyclin-dependent kinase inhibitors p16 and p21, or the cell cycle inhibitor p53, which are all upregulated in astrocytes/glial cells in experimental and human ALS [ 76 , 156 ]. In humans, current senotherapeutics do not clear specific senescent CNS cell types such as those of the NVU, but instead act on senescent burden, mainly alleviating the overall proinflammatory microenvironment.…”

Section: Targeting Brain Vascular Health To Preserve Microvascular In...mentioning

confidence: 99%

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Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

Schreiber

Bernal

Ulbrich

et al. 2023

Cells

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Brain vascular health appears to be critical for preventing the development of amyotrophic lateral sclerosis (ALS) and slowing its progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in their small cerebral blood vessels. Impaired vascular brain health has detrimental effects on motor neurons: vascular endothelial growth factor levels are lowered in ALS, which can compromise endothelial cell formation and the integrity of the blood–brain barrier. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.

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“…SASP leads to immune cell recruitment, particularly via interleukin (IL)-6 and IL-8 secretion, and overall creates a local microenvironment that promotes senescence dissemination, i.e. imparts stress on surrounding cells, and chronic (inflammatory) tissue damage, which in turn drives chronic low-grade neuroinflammation and finally neurodegeneration [76,77]. Indeed, immunosenescence, e.g.…”

Section: Factors Downstream Of Cell Activation In the Neurovascular Unitmentioning

confidence: 99%

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

Schreiber¹,

Bernal²,

Ulbrich³

et al. 2023

Preprint

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Brain vascular health appears to be of critical importance for protection against the development of amyotrophic lateral sclerosis (ALS) as well as the slowing of disease progression. ALS patients often demonstrate cardiovascular risk factors and commonly suffer from cerebrovascular disease, with evidence of pathological alterations in the small cerebral vessels. Impaired vascular brain health has detrimental effects on motor neurons as lowered vascular endothelial growth factor levels compromise endothelial cell formation, promoting blood-brain barrier leakage and inflammation. Increased turnover of neurovascular unit cells precedes their senescence, which, together with pericyte alterations, further fosters the failure of toxic metabolite removal. We here provide a comprehensive overview of the pathogenesis of impaired brain vascular health in ALS and how novel magnetic resonance imaging techniques can aid its detection. In particular, we discuss vascular patterns of blood supply to the motor cortex with the number of branches from the anterior and middle cerebral arteries acting as a novel marker of resistance and resilience against downstream effects of vascular risk and events in ALS. We outline how certain interventions adapted to patient needs and capabilities have the potential to mechanistically target the brain microvasculature towards favorable motor cortex blood supply patterns. Through this strategy, we aim to guide novel approaches to ALS management and a better understanding of ALS pathophysiology.

show abstract

Cellular senescence in neuroinflammatory disease: new therapies for old cells?

Cited by 23 publications

References 107 publications

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Senolytic therapy alleviates physiological human brain aging and COVID-19 neuropathology

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

Brain Vascular Health in ALS Is Mediated through Motor Cortex Microvascular Integrity

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