Microglia-Derived Extracellular Vesicles Carrying miR-711 Alleviate Neurodegeneration in a Murine Alzheimer’s Disease Model by Binding to Itpkb

Zhang, Yizhi; Xu, Chengbi; Nan, Yi; Nan, Shanji

doi:10.3389/fcell.2020.566530

Cited by 20 publications

(18 citation statements)

References 30 publications

(34 reference statements)

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“…LAMP1, RAB7, RAB27, CD63 and cathepsin B antibodies were then used to determine whether these proteins were altered in hippocampal lysates from zQ175 mice at 6 months of age, and the western blots of hippocampal lysates from 8- and 12-week-old R6/2 mice were repeated with a larger number of samples. We found that levels of RAB27 and CD63, both involved in MVB related exocytosis [ 24 , 54 , 82 ], were reduced in the 6-month-old zQ175 and 8- and 12-week-old R6/2 lysates (Fig. 8 ).…”

Section: Resultsmentioning

confidence: 94%

Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease

Zhou

Peskett

Landles

et al. 2021

acta neuropathol commun

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Huntington’s disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. We successfully adapted a high-resolution correlative light and electron microscopy methodology, originally developed for mammalian and yeast cells, to allow us to correlate light microscopy and electron microscopy images on the same brain section within an accuracy of 100 nm. Using this approach, we identified these recruitment sites as single membrane bound, vesicle-rich endolysosomal organelles, specifically as (1) multivesicular bodies (MVBs), or amphisomes and (2) autolysosomes or residual bodies. The organelles were often found in close-proximity to phagophore-like structures. Immunogold labeling localized mutant HTT to non-fibrillar, electron lucent structures within the lumen of these organelles. In presymptomatic HD, the recruitment organelles were predominantly MVBs/amphisomes, whereas in late-stage HD, there were more autolysosomes or residual bodies. Electron tomograms indicated the fusion of small vesicles with the vacuole within the lumen, suggesting that MVBs develop into residual bodies. We found that markers of MVB-related exocytosis were depleted in presymptomatic mice and throughout the disease course. This suggests that endolysosomal homeostasis has moved away from exocytosis toward lysosome fusion and degradation, in response to the need to clear the chronically aggregating mutant HTT protein, and that this occurs at an early stage in HD pathogenesis.

show abstract

Section: Resultsmentioning

confidence: 94%

Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease

Zhou

Peskett

Landles

et al. 2021

acta neuropathol commun

View full text Add to dashboard Cite

show abstract

“…LAMP1, RAB7, RAB27, CD63 and cathepsin B antibodies were then used to determine whether these proteins were altered in hippocampal lysates from zQ175 mice at 6 months of age, and the western blots of hippocampal lysates from 8- and 12-week-old R6/2 mice were repeated with a larger number of samples. We found that levels of RAB27 and CD63, both involved in MVB related exocytosis [53,23,80], were reduced in the 6-month-old zQ175 and 8- and 12-week-old R6/2 lysates (Fig. 8).…”

Section: Resultsmentioning

confidence: 94%

Correlative light and electron microscopy reveals that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease

Zhou

Peskett

Landles

et al. 2021

Preprint

View full text Add to dashboard Cite

Huntington's disease (HD) is a late onset, inherited neurodegenerative disorder for which early pathogenic events remain poorly understood. Here we show that mutant exon 1 HTT proteins are recruited to a subset of cytoplasmic aggregates in the cell bodies of neurons in brain sections from presymptomatic HD, but not wild-type, mice. This occurred in a disease stage and polyglutamine-length dependent manner. We successfully adapted a high-resolution correlative light and electron microscopy methodology, originally developed for mammalian and yeast cells, to allow us to correlate light microscopy and electron microscopy images on the same brain section within an accuracy of 100 nm. Using this approach, we identified these recruitment sites as single membrane bound, vesicle-rich endolysosomal organelles, specifically as (i) multivesicular bodies (MVBs), or amphisomes and (ii) autolysosomes or residual bodies. The organelles were often found in close proximity to phagophore-like structures. Immunogold labeling localized mutant HTT to non-fibrillar, electron lucent structures within the lumen of these organelles. In presymptomatic HD, the recruitment organelles were predominantly MVBs/amphisomes, whereas in late-stage HD, there were more autolysosomes or residual bodies. Electron tomograms indicated the fusion of small vesicles with the vacuole within the lumen, suggesting that MVBs develop into residual bodies. We found that markers of MVB-related exocytosis were depleted in presymptomatic mice and throughout the disease course. This suggests that endolysosomal homeostasis has moved away from exocytosis toward lysosome fusion and degradation, in response to the need to clear the chronically aggregating mutant HTT protein, and that this occurs at an early stage in HD pathogenesis.

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“…The role of miRNAs in microglial exosomes on regulating neurodegeneration was also demonstrated in repetitive mild TBI, important risk factor for long-term neurodegenerative disorders, such as AD. In vivo, hyperphosphorylation of Tau was reduced via injection of EVs with overexpressed miRNA-711 secreted by BV-2 human microglia cells [ 66 ]. This has been suggested to affect the neuro-immunological interactions between macrophages and sensory neurons [ 67 ].…”

Section: Neuron–microglia Crosstalk In Cns Physiology and Pathologmentioning

confidence: 99%

Epigenetics and Communication Mechanisms in Microglia Activation with a View on Technological Approaches

et al. 2021

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Microglial cells, the immune cells of the central nervous system (CNS), play a crucial role for the proper brain development and function and in CNS homeostasis. While in physiological conditions, microglia continuously check the state of brain parenchyma, in pathological conditions, microglia can show different activated phenotypes: In the early phases, microglia acquire the M2 phenotype, increasing phagocytosis and releasing neurotrophic and neuroprotective factors. In advanced phases, they acquire the M1 phenotype, becoming neurotoxic and contributing to neurodegeneration. Underlying this phenotypic change, there is a switch in the expression of specific microglial genes, in turn modulated by epigenetic changes, such as DNA methylation, histones post-translational modifications and activity of miRNAs. New roles are attributed to microglial cells, including specific communication with neurons, both through direct cell–cell contact and by release of many different molecules, either directly or indirectly, through extracellular vesicles. In this review, recent findings on the bidirectional interaction between neurons and microglia, in both physiological and pathological conditions, are highlighted, with a focus on the complex field of microglia immunomodulation through epigenetic mechanisms and/or released factors. In addition, advanced technologies used to study these mechanisms, such as microfluidic, 3D culture and in vivo imaging, are presented.

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Microglia-Derived Extracellular Vesicles Carrying miR-711 Alleviate Neurodegeneration in a Murine Alzheimer’s Disease Model by Binding to Itpkb

Cited by 20 publications

References 30 publications

Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease

Correlative light and electron microscopy suggests that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease

Correlative light and electron microscopy reveals that mutant huntingtin dysregulates the endolysosomal pathway in presymptomatic Huntington’s disease

Epigenetics and Communication Mechanisms in Microglia Activation with a View on Technological Approaches

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