Increased oxidative stress, hyperphosphorylation of tau, and dystrophic microglia in the hippocampus of aged <scp><i>Tupaia belangeri</i></scp>

Rodríguez-Callejas, Juan D.; Fuchs, Eberhard; Pérez-Cruz, Claudia

doi:10.1002/glia.23804

Cited by 27 publications

(27 citation statements)

References 116 publications

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“…In Cynomolgus macaques exposed to chronic manganese to model Parkinson’s disease-related pathology, dystrophic microglia were found to have intracellular ferric iron [32], which is in agreement with our findings that FTL is highly expressed in dystrophic microglia. Dystrophic microglia have been shown to increase with age in tree shrews ( Tupaia belangeri) [33], which is in agreement with our findings. Interestingly, ferritin labeled microglia was high in oxidative stress markers and had internalized hyperphosphorylated tau [33].…”

Section: Discussionsupporting

confidence: 93%

“…Dystrophic microglia have been shown to increase with age in tree shrews ( Tupaia belangeri) [33], which is in agreement with our findings. Interestingly, ferritin labeled microglia was high in oxidative stress markers and had internalized hyperphosphorylated tau [33]. In mice dystrophic microglia are seldom reported; however, a recent study did find in a mouse model of P301S tauopathy, a decrease in microglia complexity in the tau mouse with age, which could be contributed to a dystrophic microglia morphology [34].…”

Section: Discussionsupporting

confidence: 93%

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Dystrophic microglia are a disease associated microglia morphology in the human brain

et al. 2020

Preprint

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Microglia activation—typically described in terms of hypertrophic appearance—is a well-established feature of aging. Recent studies have suggested that microglia dystrophy, not activation, may increase the propagation of progressive neurodegenerative diseases such as Alzheimer’s disease (AD). Yet, a clear understanding of cause and consequences of dystrophic microglia is lacking. Although frequently observed in diseased brains, the appearance of dystrophic microglia in the hippocampus of individuals free of cognitive impairment suggests that microglia may be undergoing senescence with age, leading to dystrophy. Therefore, we hypothesized that chronological age could be a significant contributor to the presence of dystrophic microglia. To investigate this relationship, we employed stereological counts of total microglia, hypertrophic, and dystrophic microglia across the decades of the human lifespan. The microglia counts were performed in the frontal cortex gray and white matter and the CA1 subregion of the hippocampus in individuals without known neurodegenerative disease. There was age-associated increase in the number of dystrophic microglia in the CA1 region and the frontal cortex gray matter related to age. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia, suggesting that aging alone was not sufficient to explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia phenotype. Compared to controls without neuropathology, the number of dystrophic microglia was significantly greater in aged-matched cases with either AD, dementia with Lewy bodies, or LATE-NC. These results provide evidence that healthy aging is only associated with a modest increase in dystrophic microglia and suggest that dystrophic microglia may be a disease-associated microglia phenotype. Finally, we found strong evidence for iron homeostasis changes, with increases in ferritin light chain, in dystrophic microglia compared to ramified or hypertrophic microglia. Based on our findings, microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Future work is required to understand the links between the increase in dystrophic microglia and neurodegenerative disorders.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Dystrophic microglia are a disease associated microglia morphology in the human brain

et al. 2020

Preprint

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“…HSV-1 might become opportunistic as a result, targeting the hippocampus when microglial immunosurveillance weakens. This is consistent with the findings that senescence or aged microglia often preceded AD-related neuropathology in the brain, including the hippocampus (Kaneshwaran et al, 2019;Rodriguez-Callejas et al, 2020), as also reviewed in Streit et al (2009). Henceforth, specific antiviral immunity against HSV-1 might be inadequate in brain regions susceptible to HSV-1 infection.…”

Section: Inadequate Antiviral Immunitysupporting

confidence: 88%

The Hippocampal Vulnerability to Herpes Simplex Virus Type I Infection: Relevance to Alzheimer’s Disease and Memory Impairment

Yong

Teoh

et al. 2021

Front. Cell. Neurosci.

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Herpes simplex virus type 1 (HSV-1) as a possible infectious etiology in Alzheimer’s disease (AD) has been proposed since the 1980s. The accumulating research thus far continues to support the association and a possible causal role of HSV-1 in the development of AD. HSV-1 has been shown to induce neuropathological and behavioral changes of AD, such as amyloid-beta accumulation, tau hyperphosphorylation, as well as memory and learning impairments in experimental settings. However, a neuroanatomical standpoint of HSV-1 tropism in the brain has not been emphasized in detail. In this review, we propose that the hippocampal vulnerability to HSV-1 infection plays a part in the development of AD and amnestic mild cognitive impairment (aMCI). Henceforth, this review draws on human studies to bridge HSV-1 to hippocampal-related brain disorders, namely AD and aMCI/MCI. Next, experimental models and clinical observations supporting the neurotropism or predilection of HSV-1 to infect the hippocampus are examined. Following this, factors and mechanisms predisposing the hippocampus to HSV-1 infection are discussed. In brief, the hippocampus has high levels of viral cellular receptors, neural stem or progenitor cells (NSCs/NPCs), glucocorticoid receptors (GRs) and amyloid precursor protein (APP) that support HSV-1 infectivity, as well as inadequate antiviral immunity against HSV-1. Currently, the established diseases HSV-1 causes are mucocutaneous lesions and encephalitis; however, this review revises that HSV-1 may also induce and/or contribute to hippocampal-related brain disorders, especially AD and aMCI/MCI.

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“…Aged canine microglial cells also were characterized by clustering, abnormalities in cytoplasmic structure, deramified, fragmented, or tortuous processes, and occasional spheroidal or bulbous swellings [ 81 ]. Like NHP, old tree shrews (8 years) presented with an increased number of ferritin-positive and dystrophic microglia compared to adult animals (4 years) [ 82 ].…”

Section: Microglia In Agingmentioning

confidence: 99%

Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review

Edler

Mhatre-Winters

Richardson

2021

Cells

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Microglia are the primary immune cells of the central nervous system that help nourish and support neurons, clear debris, and respond to foreign stimuli. Greatly impacted by their environment, microglia go through rapid changes in cell shape, gene expression, and functional behavior during states of infection, trauma, and neurodegeneration. Aging also has a profound effect on microglia, leading to chronic inflammation and an increase in the brain’s susceptibility to neurodegenerative processes that occur in Alzheimer’s disease. Despite the scientific community’s growing knowledge in the field of neuroinflammation, the overall success rate of drug treatment for age-related and neurodegenerative diseases remains incredibly low. Potential reasons for the lack of translation from animal models to the clinic include the use of a single species model, an assumption of similarity in humans, and ignoring contradictory data or information from other species. To aid in the selection of validated and predictive animal models and to bridge the translational gap, this review evaluates similarities and differences among species in microglial activation and density, morphology and phenotype, cytokine expression, phagocytosis, and production of oxidative species in aging and Alzheimer’s disease.

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Increased oxidative stress, hyperphosphorylation of tau, and dystrophic microglia in the hippocampus of aged Tupaia belangeri

Cited by 27 publications

References 116 publications

Dystrophic microglia are a disease associated microglia morphology in the human brain

Dystrophic microglia are a disease associated microglia morphology in the human brain

The Hippocampal Vulnerability to Herpes Simplex Virus Type I Infection: Relevance to Alzheimer’s Disease and Memory Impairment

Microglia in Aging and Alzheimer’s Disease: A Comparative Species Review

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