NIA workshop on senescence in brain aging and Alzheimer’s disease and its related dementias

DiBattista, Amanda M.; Sierra, Felipe; Masliah, Eliezer

doi:10.1007/s11357-020-00153-9

Cited by 9 publications

(5 citation statements)

References 7 publications

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“…Accumulating evidence indicates that cellular senescence is involved in the etiology of age-related diseases such as Alzheimer's disease [52,53]. Defining the impact of accumulation of senescent cells in the brain and their removal is of paramount importance for our understanding of AD and AD-related dementias [54].…”

Section: Discussionmentioning

confidence: 99%

Brain cellular senescence in mouse models of Alzheimer’s disease

Dorigatti

Riordan

et al. 2022

GeroScience

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The accumulation of senescent cells contributes to aging pathologies, including neurodegenerative diseases, and its selective removal improves physiological and cognitive function in wild-type mice as well as in Alzheimer's disease (AD) models. AD models recapitulate some, but not all components of disease and do so at different rates. Whether brain cellular senescence is recapitulated in some or all AD models and whether the emergence of cellular senescence in AD mouse models occurs before or after the expected onset of AD-like cognitive deficits in these models are not yet known. The goal of this study was to identify mouse models of AD and AD-related dementias that develop measurable markers of cellular senescence in brain and thus may be useful to study the role of cellular senescence in these conditions. We measured the levels of cellular senescence markers in the brains of P301S(PS19), P301L, hTau, and 3xTg-AD mice that model amyloidopathy and/or tauopathy in AD and related dementias and in wild-type, agematched control mice for each strain. Expression of cellular senescence markers in brains of transgenic P301L and 3xTg-AD mice was largely indistinguishable from that in WT control age-matched mice. In contrast, markers of cellular senescence were differentially increased in brains of transgenic hTau and P301S(PS19) mice as compared to WT control mice before the onset of ADlike cognitive deficits. Taken together, our data suggest that P301S(PS19) and hTau mice may be useful models for the study of brain cellular senescence in tauopathies including, but not limited to, AD.

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Section: Discussionmentioning

confidence: 99%

Brain cellular senescence in mouse models of Alzheimer’s disease

Dorigatti

Riordan

et al. 2022

GeroScience

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“…Moreover, BBB disruption reduces the clearance of interstitial solutes from the brain and could result in accumulation of toxic waste products, such as amyloid-β (Aβ) in case of Alzheimer's disease (AD) (Burgmans et al 2013). Aβ was found to further impair neurovascular functioning and the cerebral circulation, even before the actual formation of plaques, suggesting that these neurovascular alterations are an early event in the pathological cascade (DiBattista et al 2020;Iadecola et al 1999;Niwa et al 2002a;Niwa et al 2002b). Imaging studies also support that neurovascular dysfunction and BBB disruption occur early in the development of AD (Iturria-Medina et al 2016;Montagne et al 2015;Montagne et al 2016;van de Haar et al 2016a).…”

Section: Introductionmentioning

confidence: 99%

Increase in blood–brain barrier leakage in healthy, older adults

et al. 2020

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Blood–brain barrier (BBB) breakdown can disrupt nutrient supply and waste removal, which affects neuronal functioning. Currently, dynamic contrast-enhanced (DCE) MRI is the preferred in-vivo method to quantify BBB leakage. Dedicated DCE MRI studies in normal aging individuals are lacking, which could hamper value estimation and interpretation of leakage rate in pathological conditions. Therefore, we applied DCE MRI to investigate the association between BBB disruption and age in a healthy sample. Fifty-seven cognitively and neurologically healthy, middle-aged to older participants (mean age: 66 years, range: 47–91 years) underwent MRI, including DCE MRI with intravenous injection of a gadolinium-based contrast agent. Pharmacokinetic modeling was applied to contrast concentration time-curves to estimate BBB leakage rate in each voxel. Subsequently, leakage rate was calculated in the white and gray matter, and primary (basic sensory and motor functions), secondary (association areas), and tertiary (higher-order cognition) brain regions. A difference in vulnerability to deterioration was expected between these regions, with especially tertiary regions being affected by age. Higher BBB leakage rate was significantly associated with older age in the white and gray matter, and also in tertiary, but not in primary or secondary brain regions. Even in healthy individuals, BBB disruption was stronger in older persons, which suggests BBB disruption is a normal physiologically aging phenomenon. Age-related increase in BBB disruption occurred especially in brain regions most vulnerable to age-related deterioration, which may indicate that BBB disruption is an underlying mechanism of normal age-related decline. Netherlands Trial Register number: NL6358, date of registration: 2017-03-24.

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“…Age-related inflammation may promote GBM progression, as has been observed for other neoplasms [ 25 ]. One important pathognomonic landmark of the aging brain is senescence [ 26 ]. Not surprisingly, senescence is one of the main drivers of aging, and it also supports cancer progression.…”

Section: Aging Is a Risk Factor For Advanced Gbm And Treatment Resmentioning

confidence: 99%

Residual Disease in Glioma Recurrence: A Dangerous Liaison with Senescence

Putavet

Keizer

2021

Cancers

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With a dismally low median survival of less than two years after diagnosis, Glioblastoma (GBM) is the most lethal type of brain cancer. The standard-of-care of surgical resection, followed by DNA-damaging chemo-/radiotherapy, is often non-curative. In part, this is because individual cells close to the resection border remain alive and eventually undergo renewed proliferation. These residual, therapy-resistant cells lead to rapid recurrence, against which no effective treatment exists to date. Thus, new experimental approaches need to be developed against residual disease to prevent GBM survival and recurrence. Cellular senescence is an attractive area for the development of such new approaches. Senescence can occur in healthy cells when they are irreparably damaged. Senescent cells develop a chronic secretory phenotype that is generally considered pro-tumorigenic and pro-migratory. Age is a negative prognostic factor for GBM stage, and, with age, senescence steadily increases. Moreover, chemo-/radiotherapy can provide an additional increase in senescence close to the tumor. In light of this, we will review the importance of senescence in the tumor-supportive brain parenchyma, focusing on the invasion and growth of GBM in residual disease. We will propose a future direction on the application of anti-senescence therapies against recurrent GBM.

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NIA workshop on senescence in brain aging and Alzheimer’s disease and its related dementias

Cited by 9 publications

References 7 publications

Brain cellular senescence in mouse models of Alzheimer’s disease

Brain cellular senescence in mouse models of Alzheimer’s disease

Increase in blood–brain barrier leakage in healthy, older adults

Residual Disease in Glioma Recurrence: A Dangerous Liaison with Senescence

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