Cellular senescence at the crossroads of inflammation and Alzheimer's disease

Guerrero, Ana Tereza Gomes; Strooper, Bart De; Arancibia-Cárcamo, I. Lorena

doi:10.1016/j.tins.2021.06.007

Cited by 152 publications

(120 citation statements)

References 175 publications

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“…Some genes mediate increased phagocytic function in these glia, whereas other genes allot glia towards adopting proinflammatory states leading to chronic damage and cell death. Recently, the evidence for possible roles of glia and senescence in AD was explored 5,6 .…”

Section: Introductionmentioning

confidence: 99%

“…Senescence is also reliably implicated in aging and accelerated mortality 11,24 , where senolytic drugs targeting and removing senescent cells have been shown to increase the lifespan and quality of life in mice [25][26][27][28] . Although senescence has been reviewed in terms of potential association with LOAD 5,6,[29][30][31] , how senescence relates to LOAD and Braak staging particularly is not well defined. Here, LOAD is uniquely hypothesized as a disease that progresses based on the severity of glial aging and senescence accumulation.…”

mentioning

confidence: 99%

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The Glial Aging & Senescence Hypothesis of Late-onset Alzheimer’s

Lau¹,

Ramer²,

Tremblay³

2022

Preprint

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Alzheimer’s disease (AD) predominantly occurs as a late-onset form (LOAD), involving neurodegeneration and cognitive decline with progressive memory loss. Over time, risk factors and aging promote accumulation of well-known AD pathologies in oxidative stress, amyloid-beta and tau protein pathology, as well as inflammation. Homeostatic glial functions regulate and suppress these AD pathologies; however, other glial states involve increased pro-inflammatory cytokine release and further pathology accumulation. Different stresses can additionally induce cellular senescence, or an irreversible differentiation process resulting in decreased supportive functions and increased, pro-inflammatory cytokine release. While these pathophysiological underpinnings all contribute to LOAD, they require temporal and mechanistic integration. This perspective hypothesizes that when individuals have threshold senescent glia accumulation, they transition from healthy cognition into mild cognitive impairment and LOAD diagnosis. Particularly, senescent microglia are predicted to represent a final threshold required for the tau pathology burden and spreading that corresponds to sustained neurodegeneration and dementia severity. We first explore age-related decline in glia that promote increases in AD pathologies, and then discuss emerging evidence linking oxidative stress, neurons containing tau pathology, and amyloid-beta to microglia, oligodendrocyte progenitor cell, and astrocyte senescence. Our hypothesis proposes that senescent astrocytes and oligodendrocyte progenitors pressure microglia to phagocytose neurons containing tau pathology. The resulting senescent microglia would form neuritic plaques and induce paracrine senescence transitioning into a progressive clinical dementia presentation. This predictive hypothesis can potentially account for why medications used to treat LOAD fail, as previous treatments have not reduced senescent glial burden. It is also coherent with the predominant hypotheses surrounding LOAD, generates testable hypotheses about LOAD, and increases rationale in testing senolytics as targeted treatments for LOAD arrest and reversal.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

The Glial Aging & Senescence Hypothesis of Late-onset Alzheimer’s

Lau¹,

Ramer²,

Tremblay³

2022

Preprint

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“… 7 , 13 , 14 Noteworthy, genetic ablation and/or pharmacological blockade of microglia shows neuroprotective effect in neurodegenerative diseases. 15 , 16 …”

Section: Introductionmentioning

confidence: 99%

“…7,13,14 Noteworthy, genetic ablation and/or pharmacological blockade of microglia shows neuroprotective effect in neurodegenerative diseases. 15,16 Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD)-dependent deacetylase, deacetylates transcription factors, signaling molecules, and histones. 17,18 Resveratrol enhances SIRT1 activity via promoting NADH oxidation to NAD+ and, possibly, by boosting SIRT1 affinity for NAD+ as well as acetylated substrate.…”

Section: Introductionmentioning

confidence: 99%

Modulation of Sirt1-mTORC1 Pathway in Microglia Attenuates Retinal Ganglion Cell Loss After Optic Nerve Injury

Mou¹,

Yao²,

Ye³

et al. 2021

JIR

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Purpose Optic nerve injury (ONI) causes neuroinflammation and neurodegeneration leading to visual deficits. The response of microglia has emerged as an impactful component of etiology in neurodegeneration. This study aimed to investigate the effect of SIRT1-mTORC1 signaling pathway in microglia regulation after ONI. Methods Cx3Cr1-Cre ERT2 / Raptor F/F and Cx3Cr1-Cre ERT2 / Sirt1 F/F mice were used to delete Raptor and Sirt1 in microglia, respectively. Optic nerve crush (ONC) model was established to mimic ONI. PLX5622, a highly specific inhibitor of the colony-stimulating factor 1 receptor (CSF1R), is used to eliminate microglia in optic nerve. Ionized calcium binding adaptor molecule 1 (Iba1) immunostaining was used to detect microglial activation. Retinal ganglion cells (RGCs) were quantified by Nissl staining and retinal whole-mount immunostaining with RNA-binding protein with multiple splicing (RBPMS). Axonal damage was valued by transmission electron microscopy (TEM). Results Microglial activation emerged on day 3 post ONC and was earlier than RGCs loss which occurred at day 5 after injury. Depleting microglia with PLX5622 could attenuate the loss of RGCs and axon damage after ONC. Gain- and loss-of-function studies revealed that SIRT1 determined the activation of microglia in optic nerve. In addition, microglia-specific deletion of Raptor resulted in decreased microglial activation. Interestingly, activating mTORC1 with CCT007093 could reverse the function of SIRT1 in regulating the process of microglial activation mediated RGCs loss. Conclusion Our study reveals a potential novel mechanism of SIRT1-mTORC1 pathway in microglia regulation, and indicates a therapeutic potential for the protection of RGCs in ONI.

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“…The central nervous system (CNS) undergoes numerous detrimental transformations with age such as mitochondrial dysfunction, oxidative stress, and chronic inflammation ( Chakrabarti et al, 2011 ; Maciel-Barón et al, 2018b ) and the presence of senescent cells has been associated with neurodegenerative diseases including Alzheimer’s disease (AD), Parkinson’s disease (PD), and HIV-dementia ( Bhat et al, 2012 ; Chinta et al, 2015 , 2018 ; Cohen et al, 2018 ; Guerrero et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons

Morales-Rosales

Santín-Márquez

Posadas-Rodríguez

et al. 2021

Front. Aging Neurosci.

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The decline in brain function during aging is one of the most critical health problems nowadays. Although senescent astrocytes have been found in old-age brains and neurodegenerative diseases, their impact on the function of other cerebral cell types is unknown. The aim of this study was to evaluate the effect of senescent astrocytes on the mitochondrial function of a neuron. In order to evaluate neuronal susceptibility to a long and constant senescence-associated secretory phenotype (SASP) exposure, we developed a model by using cellular cocultures in transwell plates. Rat primary cortical astrocytes were seeded in transwell inserts and induced to premature senescence with hydrogen peroxide [stress-induced premature senescence (SIPS)]. Independently, primary rat cortical neurons were seeded at the bottom of transwells. After neuronal 6 days in vitro (DIV), the inserts with SIPS-astrocytes were placed in the chamber and cocultured with neurons for 6 more days. The neuronal viability, the redox state [reduced glutathione/oxidized glutathione (GSH/GSSG)], the mitochondrial morphology, and the proteins and membrane potential were determined. Our results showed that the neuronal mitochondria functionality was altered after being cocultured with senescent astrocytes. In vivo, we found that old animals had diminished mitochondrial oxidative phosphorylation (OXPHOS) proteins, redox state, and senescence markers as compared to young rats, suggesting effects of the senescent astrocytes similar to the ones we observed in vitro. Overall, these results indicate that the microenvironment generated by senescent astrocytes can affect neuronal mitochondria and physiology.

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Cellular senescence at the crossroads of inflammation and Alzheimer's disease

Cited by 152 publications

References 175 publications

The Glial Aging & Senescence Hypothesis of Late-onset Alzheimer’s

The Glial Aging & Senescence Hypothesis of Late-onset Alzheimer’s

Modulation of Sirt1-mTORC1 Pathway in Microglia Attenuates Retinal Ganglion Cell Loss After Optic Nerve Injury

Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons

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