Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain

Shahidehpour, Ryan K.; Higdon, Rebecca E.; Crawford, Nicole G.; Neltner, Janna H.; Ighodaro, Eseosa T.; Patel, Ela; Price, Douglas A.; Nelson, Peter T.; Bachstetter, Adam D.

doi:10.1016/j.neurobiolaging.2020.12.003

Cited by 127 publications

(108 citation statements)

References 35 publications

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“…Conversely, the number of dystrophic microglia was significantly increased in patients suffering from neurodegenerative disorders. Consistent with the data of Shahidehpour et al (36), ferritin is expressed in the OA2 subpopulation (12), which again is minimal in the absence of overt pathology, yet abundant in neurodegenerative disease conditions (DAM) (52). Taken together, the data suggests a disease-induced increase of cellular aging hallmarks.…”

Section: Gradual Accumulation Of Dam During Agingsupporting

confidence: 89%

“…However, recently some light has been shed on the question whether these two terms are describing the same or two different phenotypes. To address this issue, Shahidehpour et al ( 36 ) conducted stereological analysis of microglia in human brain tissue spanning the age of 10-90 years. The analysis revealed an increased number of dystrophic microglia with age, which, however, was much greater when neurodegenerative pathology was present as well ( 36 ).…”

Section: Microglial Aging: a Summation Of Factors Accumulated Throughout Life?mentioning

confidence: 99%

“…To address this issue, Shahidehpour et al ( 36 ) conducted stereological analysis of microglia in human brain tissue spanning the age of 10-90 years. The analysis revealed an increased number of dystrophic microglia with age, which, however, was much greater when neurodegenerative pathology was present as well ( 36 ). They hence conclude that aging itself is only associated with a minor increase in dystrophic microglia ( 36 ).…”

Section: Microglial Aging: a Summation Of Factors Accumulated Throughout Life?mentioning

confidence: 99%

“…The analysis revealed an increased number of dystrophic microglia with age, which, however, was much greater when neurodegenerative pathology was present as well ( 36 ). They hence conclude that aging itself is only associated with a minor increase in dystrophic microglia ( 36 ). It is thus possible that the disease event that generated an activated microglia phenotype, potentially early in life, has a priming effect on cellular aging, leading to an increase of dystrophic microglia in old age ( Figure 1A ).…”

Section: Microglial Aging: a Summation Of Factors Accumulated Throughout Life?mentioning

confidence: 99%

“…IRM (consistent with OA3) conversely seemed to increase with age more rapidly in App NL − G − F mice than wild-type mice but ultimately also represented only a minority of cells (< ~5%) similar to wild-type mice. Ferretin expression has been identified as a marker for dystrophic microglia ( 36 ) and senescence ( 26 ). Shahidehpour and colleagues ( 36 ) found ferretin-expressing dystrophic cells to be present, but again to a very small extent, in healthy aged humans.…”

Section: Gradual Accumulation Of Dam During Agingmentioning

confidence: 99%

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Microglia Phenotypes Converge in Aging and Neurodegenerative Disease

Candlish

Hefendehl

2021

Front. Neurol.

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Microglia, the primary immune cells of the central nervous system, hold a multitude of tasks in order to ensure brain homeostasis and are one of the best predictors of biological age on a cellular level. We and others have shown that these long-lived cells undergo an aging process that impedes their ability to perform some of the most vital homeostatic functions such as immune surveillance, acute injury response, and clearance of debris. Microglia have been described as gradually transitioning from a homeostatic state to an activated state in response to various insults, as well as aging. However, microglia show diverse responses to presented stimuli in the form of acute injury or chronic disease. This complexity is potentially further compounded by the distinct alterations that globally occur in the aging process. In this review, we discuss factors that may contribute to microglial aging, as well as transcriptional microglia alterations that occur in old age. We then compare these distinct phenotypic changes with microglial phenotype in neurodegenerative disease.

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Section: Gradual Accumulation Of Dam During Agingsupporting

confidence: 89%

Section: Microglial Aging: a Summation Of Factors Accumulated Throughout Life?mentioning

confidence: 99%

Section: Microglial Aging: a Summation Of Factors Accumulated Throughout Life?mentioning

confidence: 99%

Section: Microglial Aging: a Summation Of Factors Accumulated Throughout Life?mentioning

confidence: 99%

Section: Gradual Accumulation Of Dam During Agingmentioning

confidence: 99%

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Microglia Phenotypes Converge in Aging and Neurodegenerative Disease

Candlish

Hefendehl

2021

Front. Neurol.

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Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies

Gaikwad,

Senapati,

Haque

et al. 2023

Alzheimer's & Dementia

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Aging, tau pathology, and chronic inflammation in the brain play crucial roles in synaptic loss, neurodegeneration, and cognitive decline in tauopathies, including Alzheimer's disease. Senescent cells accumulate in the aging brain, accelerate the aging process, and promote tauopathy progression through their abnormal inflammatory secretome known as the senescence‐associated secretory phenotype (SASP). Tau oligomers (TauO)—the most neurotoxic tau species—are known to induce senescence and the SASP, which subsequently promote neuropathology, inflammation, oxidative stress, synaptic dysfunction, neuronal death, and cognitive dysfunction. TauO, brain inflammation, and senescence are associated with heterogeneity in tauopathy progression and cognitive decline. However, the underlying mechanisms driving the disease heterogeneity remain largely unknown, impeding the development of therapies for tauopathies. Based on clinical and preclinical evidence, this review highlights the critical role of TauO and senescence in neurodegeneration. We discuss key knowledge gaps and potential strategies for targeting senescence and TauO to treat tauopathies.Highlights Senescence, oligomeric Tau (TauO), and brain inflammation accelerate the aging process and promote the progression of tauopathies, including Alzheimer's disease. We discuss their role in contributing to heterogeneity in tauopathy and cognitive decline. We highlight strategies to target senescence and TauO to treat tauopathies while addressing key knowledge gaps.

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Is microglial dystrophy a form of cellular senescence? An analysis of senescence markers in the aged human brain

Neumann

Lenz

Streit

et al. 2022

Glia

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Aging can cause morphological transformation in human microglia indicative of cell senescence, termed microglial dystrophy. However, cellular senescence is characterized by additional changes, such as an irregular cell cycle arrest, and a variety of metabolic and molecular changes including a senescence-associated secretory phenotype, dysfunction of degradation mechanisms, and altered DNA damage response. Here, we tested whether dystrophic microglia display customary markers of cell senescence by performing double and triple staining in sections of the temporal lobe and brain stem from 14 humans. We found that markers related to oxidative damage, such as upregulation of 8-hydroxy-2 0 -deoxyguanosine (8-OHdG), hemeoxygenase-1 (HO-1), and y-H2AX, as well as inclusion of lipofuscin, do not or only exceptionally colocalize with dystrophic microglia. Further, we did not observe a decline in lamin B1 around nuclear laminae in either dystrophic or ramified microglia within the same microscopic field.Only ferritin expression, which is known to increase with aging in CNS microglia, was frequently observed in dystrophic, but rarely in ramified microglial cells. We conclude that neither dystrophic nor ramified microglia in human brain exhibit significant expression of conventional senescence markers associated with oxidative stress, and that ferritin is the dominant immunophenotypic change related to microglial aging. We suggest that multiple pathogenic mechanisms other than those driving cellular senescence contribute to dystrophic transformation of microglia.

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Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain

Cited by 127 publications

References 35 publications

Microglia Phenotypes Converge in Aging and Neurodegenerative Disease

Microglia Phenotypes Converge in Aging and Neurodegenerative Disease

Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies

Is microglial dystrophy a form of cellular senescence? An analysis of senescence markers in the aged human brain

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