Age and gender effects on microglia and astrocyte numbers in brains of mice

Mouton, Peter R.; Long, Jeffrey M.; Lei, De-Liang; Howard, Victor; Jucker, Mathias; Calhoun, Michael E.; Ingram, Donald K.

doi:10.1016/s0006-8993(02)03475-3

Cited by 283 publications

(221 citation statements)

References 31 publications

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“…Since our results suggested that microglia clear away the myelin fragments that accumulate in the 3 aging brain, we compared microglia number and appearance in young and old animals. Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2).…”

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confidence: 79%

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Age-related myelin degradation burdens the clearance function of microglia during aging

Kannaiyan²,

et al. 2016

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2Myelin is synthesized as a multilamellar membrane, but the mechanisms of membrane turnover are unknown. We find that myelin pieces are gradually released from aging myelin sheaths and are subsequently cleared by microglia. Myelin fragmentation increases with age and leads to the formation of insoluble, lipofuscin-like lysosomal inclusions in microglia. Thus, age-related myelin fragmentation is substantial leading to lysosomal storage and contributing to microglia senescence and immune dysfunction in aging.Myelin is formed by oligodendrocytes as a multilamellar structure that encloses segments of axons in the central nervous systems (CNS) of vertebrates 1 . Once myelin is laid down, it is unknown to what extent the sheaths require maintenance and remodeling. Membrane turnover may pose a problem for oligodendrocytes that form up to 80 different myelin sheaths of tightly stacked membrane, but harbour little cytoplasm and few lysosomes, the organelles responsible for membrane degradation. Myelin membrane components are metabolically relatively stable with half-lives on the order of several weeks to months 2,3 . Nevertheless, protein/lipid turnover is, in general, necessary to replace potentially impaired molecules with new functional copies in order to combat functional decline [4][5][6][7] . How do molecules trapped within the numerous layers of tightly compacted membrane enter the degradative system? We tested the hypothesis that myelin degradation occurs in part via shedding of myelin fragments into the extracellular space.We analyzed the white matter of aging mice (up to 24 months) by electron microscopy to search for myelin breakdown products. We detected multilamellar myelin fragments more frequently in the brain of the older mice, of which some were associated with myelin sheaths, while others were in the extracellular space or inside of cells (Supplementary Fig. 1). As fixation artefacts frequently affect the appearance of myelin in chemically fixed tissue, we used high-pressure freezing to fix tissue and confirmed the progressive accumulation of multilamellar myelin fragments with age ( Fig. 1a,b).Since some of these myelin fragments were found inside cells, we performed immunhistochemistry to determine whether microglia, the brain phagocytes [8][9][10] , were responsible for the uptake of myelin fragments. An increasing number of myelin basic protein (MBP) and proteolipid protein (PLP) immunoreactive puncta co-localized with Iba1-positive microglia with age ( Fig. 1c, Supplementary Fig. 1).Three-dimensional reconstructions demonstrated that immunoreactive puncta were present inside of microglia (Fig. 1c). Since our results suggested that microglia clear away the myelin fragments that accumulate in the 3 aging brain, we compared microglia number and appearance in young and old animals. Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2). Next, the morphology of lysosomes was evalua...

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supporting

confidence: 79%

“…Not only had the number of microglia increased in the white matter of old animals as reported previously 11,12 , but also microglia in contact with myelin ( Supplementary Fig. 2).…”

supporting

confidence: 79%

Age-related myelin degradation burdens the clearance function of microglia during aging

Kannaiyan²,

et al. 2016

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“…For example, in rat retinal preparations, aging was associated with a decrease in the total number of astrocytes and with an increase in the proportion of cells with gliotic morphology. 159,160 Conversely, a rather significant (by one third) increase in the number of astrocytes was observed in hippocampus of female B57 mice 161 ; similar age-dependent increase in astrocytes quantity was found in the CA1 hippocampal area and in the frontal cortex of male Sprague-Dawley rats; this was accompanied with hypertrophic remodeling that was more prominent in the cortex. 162 An increase (by ϳ20%) in the number of astrocytes was detected in parietal cortex and the dentate gyrus of old Wistar rats.…”

Section: Morphology and Numbersmentioning

confidence: 63%

Astrocytes in Alzheimer's Disease

et al. 2010

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Summary:The circuitry of the human brain is formed by neuronal networks embedded into astroglial syncytia. The astrocytes perform numerous functions, providing for the overall brain homeostasis, assisting in neurogenesis, determining the micro-architecture of the grey matter, and defending the brain through evolutionary conserved astrogliosis programs.Astroglial cells are engaged in neurological diseases by determining the progression and outcome of neuropathological process. Astrocytes are specifically involved in various neurodegenerative diseases, including Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and various forms of dementia. Recent evidence suggest that early stages of neurodegenerative processes are associated with atrophy of astroglia, which causes disruptions in synaptic connectivity, disbalance in neurotransmitter homeostasis, and neuronal death through increased excitotoxicity. At the later stages, astrocytes become activated and contribute to the neuroinflammatory component of neurodegeneration.

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“…Quantification of total numbers of GFAP-positive astrocytes used the optical disector method, as Fig. 2 a-g Low power photomicrographs of serial sections through the entire mouse hippocampus; sections were cut at an instrument setting of 50 μm and stained with CV detailed previously (West 1993;Subbiah et al 1996;Mouton et al 1997Mouton et al , 2002Jankowsky et al 2003; for review Cavalieri 1635 with reprint 1966).…”

Section: Methodsmentioning

confidence: 99%

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

Manaye

Wang

O’Neil

et al. 2007

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Murine models that mimic the neuropathology of Alzheimer's disease (AD) have the potential to provide insight into the pathogenesis of the disease and lead to new strategies for the therapeutic management of afflicted patients. We used magnetic resonance imaging (MRI), design-based stereology, and high performance liquid chromatography (HPLC) to assess the age-related neuropathology in double transgenic mice that overexpress two AD-related proteins-amyloid precursor protein (APP) and presenilin 1 (PS1)-and age-and gender-matched wild-type (WT) controls. In mice ranging in age from 4-28 months, total volumes of the hippocampal formation (V HF ) and whole brain (V brain ) were quantified by the Cavalieri-point counting method on a systematic-random sample of coronal T2-weighted MRI images; the same stereological methods were used to quantify V HF and V brain after perfusion and histological processing. To assess changes in ADtype beta-amyloid (Aβ) plaques, sections from the hippocampal formation and amylgdaloid complex of mice aged 5, 12, and 15 months were stained by Congo Red histochemistry. In aged mice with large numbers of amyloid plaques, systematic-random samples of sections were stained by GFAP immunocytochemistry to assess gender and genotype effects on total numbers of astrocytes. In addition, levels of norepinephrine (NE), dopamine (DA), serotonin (5-HT) and 5-HT metabolites were assayed by HPLC in fresh-frozen samples from neocortex, striatum, hippocampus, and brainstem. We confirmed age-related increases in amyloid plaques, beginning with a few plaques at 5 months of age and increasing densities by AGE (2007) 12 and 15 months. At 15 months of age, there were robust genotype effects, but no gender effects, on GFAP-immunopositive astrocytes in the amygdaloid complex and hippocampus. There were no effects on monoamine levels in all brain regions examined, and no volume changes in hippocampal formation or whole brain as quantified on either neuroimages or tissue sections. Strong correlations were present between volume estimates from MRI images and histological sections, with about 85% reduction in mean V HF or mean V brain between MRI and processed histological sections. In summary, these findings show that the double transgenic expression of AD-type mutations is associated with age-related increases in amyloid plaques and astrocytosis; however, this model does not recapitulate the cortical atrophy or neurochemical changes that are characteristic of AD.29:87-96 DOI 10.1007/s11357-007-9035-

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Age and gender effects on microglia and astrocyte numbers in brains of mice

Cited by 283 publications

References 31 publications

Age-related myelin degradation burdens the clearance function of microglia during aging

Age-related myelin degradation burdens the clearance function of microglia during aging

Astrocytes in Alzheimer's Disease

Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry

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