Small extracellular vesicles in plasma reveal molecular effects of modified Mediterranean-ketogenic diet in participants with mild cognitive impairment

Kumar, Ashish; Sharma, Mitu; Su, Yixin; Singh, Sangeeta; Hsu, Fang‐Chi; Neth, Bryan J.; Register, Thomas C.; Blennow, Kaj; Zetterberg, Henrik; Craft, Suzanne; Deep, Gagan

doi:10.1093/braincomms/fcac262

Cited by 16 publications

(48 citation statements)

References 57 publications

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“…sEV AT in the Blood Reflect Molecular Changes in the Adipose Tissue. Since sEVs are emerging as the "snapshot" of the parent cells and have been implicated in identifying the pathophysiological and molecular status of the host cells, 21,23 we assessed whether the most significantly altered pathway (amino acid metabolism) identified between sEV AT-Lean and sEV AT-DIO could reflect similar changes in mice AT. We extracted RNA from VAT of the lean and DIO mice and explored the regulation of the amino acid metabolism pathway using a PCR array.…”

Section: Resultsmentioning

confidence: 99%

“…Flow cytometry analysis was performed to characterize the isolated sEV and to confirm their purity from AT and plasma. 23 sEV were labeled with membrane-labeling dye CellBrite 488 or 647 (Biotium, California, USA) with and without the fluorescently labeled antibodies. sEV without dye were used as a control to set the gate for positively labeled sEV.…”

Section: Methodsmentioning

confidence: 99%

“…These methods were performed as reported recently. , Briefly, 200 mesh copper grids (with carbon-coated Formvar film) were activated with 100% ethanol for 20 min. Thirty μL sEV samples were fixed with an equal volume of 4% paraformaldehyde for 10 min at RT and then incubated with grids for 1 h at RT.…”

Section: Methodsmentioning

confidence: 99%

“…In the past decade, numerous studies have shown the feasibility of isolating cell/tissue-specific sEV from the biofluids, exploiting the specific markers expressed on the surface using immunoprecipitation methods. Neuron-derived sEV isolated from plasma have been shown to be valuable biomarkers for various neurodegenerative diseases and assessment of responses to treatment. − In recent studies, we have reported the usefulness of brain cells derived sEV from the plasma toward accessing the expression of various neurodegenerative biomarkers , as well as determining the molecular effects of specific dietary intervention against mild-cognitive impairment . Only limited attempts have been made to isolate and characterize adipose tissue-derived sEV (sEV AT ) from plasma.…”

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confidence: 99%

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A Liquid Biopsy-Based Approach to Isolate and Characterize Adipose Tissue-Derived Extracellular Vesicles from Blood

et al. 2023

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Obesity is a major risk factor for multiple chronic diseases. Anthropometric and imaging approaches are primarily used to assess adiposity, and there is a dearth of techniques to determine the changes in adipose tissue (AT) at the molecular level. Extracellular vesicles (EVs) have emerged as a novel and less invasive source of biomarkers for various pathologies. Furthermore, the possibility of enriching cell or tissue-specific EVs from the biofluids based on their unique surface markers has led to classifying these vesicles as “liquid biopsies”, offering valuable molecular information on hard-to-access tissues. Here, we isolated small EVs from AT (sEVAT) of lean and diet-induced obese (DIO) mice, identified unique surface proteins on sEVAT by surface shaving followed by mass spectrometry, and developed a signature of five unique proteins. Using this signature, we pulled out sEVAT from the blood of mice and validated the specificity of isolated sEVAT by measuring the expression of adiponectin, 38 adipokines on an array, and several adipose tissue-related miRNAs. Furthermore, we provided evidence of sEV applicability in disease prediction by characterizing sEVAT from the blood of lean and DIO mice. Interestingly, sEVAT‑DIO cargo showed a stronger pro-inflammatory effect on THP1 monocytes compared to sEVAT‑Lean and a significant increase in obesity-associated miRNA expression. Equally important, sEVAT cargo revealed an obesity-associated aberrant amino acid metabolism that was subsequently validated in the corresponding AT. Lastly, we show a significant increase in inflammation-related molecules in sEVAT isolated from the blood of nondiabetic obese (>30 kg/m2) individuals. Overall, the present study offers a less-invasive approach to characterize AT.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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A Liquid Biopsy-Based Approach to Isolate and Characterize Adipose Tissue-Derived Extracellular Vesicles from Blood

et al. 2023

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“…Flow cytometry: Flow cytometry analysis was performed to evaluate the percentage of typical EV tetraspanin markers following methods reported recently (53). TE were labeled with membrane labeling dye CellBrite 488 (Biotium, California, USA) with and without the CD63-APC and CD81-PE (both from BioLegend, CA, USA) antibodies.…”

Section: In Vivo 38kda Microdialysismentioning

confidence: 99%

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

Pait

Kaye

et al. 2023

Preprint

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Brain-derived extracellular vesicles (EVs) play an active role in Alzheimer's disease (AD), relaying important physiological information about their host tissues. Circulating EVs are protected from degradation, making them 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 (EVISF) were isolated via ultracentrifugation and characterized by nanoparticle tracking analysis, immunogold labeling, and flow cytometry. Mass spectrometry and proteomic analyses were performed on EVISF cargo. EVISF 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 A deposition. Genotype, age, and Aβ deposition modulated proteostasis- and immunometabolic-related pathways. Changes in the microglial EVISF 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- EVISF microglial proteome. Thus, in vivo microdialysis is a novel technique for collecting EVISF and offers a unique opportunity to explore the role of EVs in AD.

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MicroRNA expression in extracellular vesicles as a novel blood‐based biomarker for Alzheimer's disease

Kumar

Sharma

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONBrain cell–derived small extracellular vesicles (sEVs) in blood offer unique cellular and molecular information related to the onset and progression of Alzheimer's disease (AD). We simultaneously enriched six specific sEV subtypes from the plasma and analyzed a selected panel of microRNAs (miRNAs) in older adults with/without cognitive impairment.METHODSTotal sEVs were isolated from the plasma of participants with normal cognition (CN; n = 11), mild cognitive impairment (MCI; n = 11), MCI conversion to AD dementia (MCI‐AD; n = 6), and AD dementia (n = 11). Various brain cell–derived sEVs (from neurons, astrocytes, microglia, oligodendrocytes, pericytes, and endothelial cells) were enriched and analyzed for specific miRNAs.RESULTSmiRNAs in sEV subtypes differentially expressed in MCI, MCI‐AD, and AD dementia compared to the CN group clearly distinguished dementia status, with an area under the curve (AUC) > 0.90 and correlated with the temporal cortical region thickness on magnetic resonance imaging (MRI).DISCUSSIONmiRNA analyses in specific sEVs could serve as a novel blood‐based molecular biomarker for AD.Highlights Multiple brain cell–derived small extracellular vesicles (sEVs) could be isolated simultaneously from blood. MicroRNA (miRNA) expression in sEVs could detect Alzheimer's disease (AD) with high specificity and sensitivity. miRNA expression in sEVs correlated with cortical region thickness on magnetic resonance imaging (MRI). Altered expression of miRNAs in sEVCD31 and sEVPDGFRβ suggested vascular dysfunction. miRNA expression in sEVs could predict the activation state of specific brain cell types.

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Small extracellular vesicles in plasma reveal molecular effects of modified Mediterranean-ketogenic diet in participants with mild cognitive impairment

Cited by 16 publications

References 57 publications

A Liquid Biopsy-Based Approach to Isolate and Characterize Adipose Tissue-Derived Extracellular Vesicles from Blood

A Liquid Biopsy-Based Approach to Isolate and Characterize Adipose Tissue-Derived Extracellular Vesicles from Blood

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

MicroRNA expression in extracellular vesicles as a novel blood‐based biomarker for Alzheimer's disease

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