Dataset Information

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV^ISF ) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology.

ABSTRACT: Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. The internal cargo of EVs is protected from degradation, making EVs attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EV^ISF ) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labelling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EV^ISF cargo. EV^ISF were 40-150 nm in size and expressed CD63, CD9, and CD81. Using a model of cerebral amyloidosis (e.g., APPswe, PSEN1dE9 mice), we found protein concentration increased but protein diversity decreased with Aβ deposition. Genotype, age, and Aβ deposition modulated proteostasis- and immunometabolic-related pathways. Changes in the microglial EV^ISF proteome were sexually dimorphic and associated with a differential response of plaque associated microglia. We found that female APP/PS1 mice have more amyloid plaques, less plaque associated microglia, and a less robust- and diverse- EV^ISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EV^ISF and offers a unique opportunity to explore the role of EVs in AD.

SUBMITTER: Pait MC

PROVIDER: S-EPMC10774707 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV<sup>ISF</sup> ) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology.

Pait Morgan C MC Kaye Sarah D SD Su Yixin Y Kumar Ashish A Singh Sangeeta S Gironda Stephen C SC Vincent Samantha S Anwar Maria M Carroll Caitlin M CM Snipes James Andy JA Lee Jingyun J Furdui Cristina M CM Deep Gagan G Macauley Shannon L SL

Journal of extracellular vesicles 20240101 1

Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. The internal cargo of EVs is protected from degradation, making EVs attractive AD biomarkers. However, it is unclear how circulating EVs relate to EVs isolated from disease-vulnerable brain regions. We developed a novel method for collecting EVs from the hippocampal interstitial fluid (ISF) of live mice. EVs (EV<sup>ISF</sup> ) were is ...[more]

PMID: 38191961

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Project description:BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Aβ) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Aβ pathology in vivo is unclear.MethodsTo explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We used the Morris water maze and open field test to assess behavioral performance. Using immunohistochemistry and biochemical analyses, we evaluated Aβ plaque load, neuronal and synaptic damage, and gliosis. Further, we utilized confocal microscopy imaging, flow cytometry, and RNA sequencing analysis to comprehensively investigate changes in microglial responses to Aβ pathology upon Asrij depletion.ResultsAsrij depletion ameliorates cognitive impairments, Aβ deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activation. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and impedes the acquisition of a pro-inflammatory disease-associated microglia (DAM) state. Reduced levels of proinflammatory cytokines and decreased STAT3 and NF-κB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology.ConclusionsIn summary, we show that Asrij depletion ameliorates Aβ pathology, neuronal and synaptic damage, gliosis, and improves behavioral performance in APP/PS1 mice. This supports that Asrij exacerbates the AD pathology. Mechanistically, Asrij is critical for the development of DAM and promotes neuroinflammatory signaling activation in microglia, thus restricting neuroprotective microglial responses. Hence, reducing Asrij in this context may help retard AD. Our work positions Asrij as a critical molecular regulator that links microglial dysfunction to AD pathogenesis.

Dataset Information

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV^ISF ) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology.

Publications

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV<sup>ISF</sup> ) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology.

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OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EVISF ) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology.

Publications

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV&lt;sup&gt;ISF&lt;/sup&gt; ) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV^ISF ) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology.

Novel method for collecting hippocampal interstitial fluid extracellular vesicles (EV<sup>ISF</sup> ) reveals sex-dependent changes in microglial EV proteome in response to Aβ pathology.