Heat Shock-Induced Extracellular Vesicles Derived from Neural Stem Cells Confer Marked Neuroprotection Against Oxidative Stress and Amyloid-β-Caused Neurotoxicity

Huber, Christa C.; Callegari, Eduardo; Paez, María D.; Romanova, Svetlana; Wang, Hongmin

doi:10.1007/s12035-022-03055-3

Cited by 16 publications

(6 citation statements)

References 24 publications

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“…Our observations are similar to those made in metazoans suggesting this mechanism is conserved (Feng et al., 2014 ; Bewicke‐Copley et al., 2017 ; Huber et al., 2022 ). Notably, cultured human (HeLa) cells show a “bystander” effect whereby a subpopulation of (donor) cells release EVs upon heat stress, presumably because they already possess a thermotolerant property.…”

Section: Discussionsupporting

confidence: 91%

Thermotolerance in S. cerevisiae as a model to study extracellular vesicle biology

Logan,

Staton,

Oliver

et al. 2024

J of Extracellular Vesicle

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The budding yeast Saccharomyces cerevisiae is a proven model organism for elucidating conserved eukaryotic biology, but to date its extracellular vesicle (EV) biology is understudied. Here, we show yeast transmit information through the extracellular medium that increases survival when confronted with heat stress and demonstrate the EV‐enriched samples mediate this thermotolerance transfer. These samples contain vesicle‐like particles that are exosome‐sized and disrupting exosome biogenesis by targeting endosomal sorting complexes required for transport (ESCRT) machinery inhibits thermotolerance transfer. We find that Bro1, the yeast ortholog of the human exosome biomarker ALIX, is present in EV samples, and use Bro1 tagged with green fluorescent protein (GFP) to track EV release and uptake by endocytosis. Proteomics analysis reveals that heat shock protein 70 (HSP70) family proteins are enriched in EV samples that provide thermotolerance. We confirm the presence of the HSP70 ortholog stress‐seventy subunit A2 (Ssa2) in EV samples and find that mutant yeast cells lacking SSA2 produce EVs but they fail to transfer thermotolerance. We conclude that Ssa2 within exosomes shared between yeast cells contributes to thermotolerance. Through this work, we advance Saccharomyces cerevisiae as an emerging model organism for elucidating molecular details of eukaryotic EV biology and establish a role for exosomes in heat stress and proteostasis that seems to be evolutionarily conserved.

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Section: Discussionsupporting

confidence: 91%

Thermotolerance in S. cerevisiae as a model to study extracellular vesicle biology

Logan,

Staton,

Oliver

et al. 2024

J of Extracellular Vesicle

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“…The sample analysis was performed based on previously described methods [21, 22] (also see https://red.library.usd.edu/cgi/viewcontent.cgi?article=1128&context=diss-thesis). Briefly, the proteins were separated using 12% SDS-PAGE and the gel was stained with colloidal Coomassie G250 (BioRad) and destained overnight.…”

Section: Methodsmentioning

confidence: 99%

“…GO analysis of the proteins was carried out by using DAVID functional annotation tool (https://david.ncifcrf.gov/summary.jsp) as previously described [21]. The UniProt IDs for each protein were converted to their official gene IDs, with Mus musculus selected as the species.…”

Section: Gene Ontology (Go) Enrichment Analysis Of the Identified Pro...mentioning

confidence: 99%

Impaired 26S proteasome causes learning and memory deficiency and induces neuroinflammation mediated by NF-κB in mice

Huber,

Callegari,

Paez

et al. 2024

Preprint

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Aging and many neurodegenerative disorders, including Alzheimer disease (AD), show reduced proteasome activity, loss of synapses and increased neuroinflammation in the brain. However, whether proteasome dysfunction causes neuroinflammation remains less understood. Here, we studied the effect of impaired 26S proteasome on neuroinflammation in the Psmc1 knockout (KO) mice deficient of a 19S proteasome subunit selectively in the forebrain region. We initially assessed the proteasome activity in the KO and control mouse brains and performed cognitive behavioral test to the animals. The synaptosomes were isolated from the forebrain and subjected to mass spectrometric analysis of total synaptic proteins. The identified synaptic proteins were then assessed using bioinformatic approaches. To validate identified proteins, Western blot analysis and immunofluorescent staining of specific protein were utilized. To validate NF-kB mediating neuroinflammation, we administered the KO animals at 5 weeks of age with a selective NF-kB inhibitor for three weeks and then, animal behaviors and neuroinflammation were assessed when they reached to eight weeks of age. Our results revealed that impaired 26S proteasome led to AD-like cognitive deficiency and overt neuroinflammation in the synapses of the Psmc1 KO brain at eight weeks of age. Pronounced neuroinflammation also occurred in other regions and glial cells, which was confirmed by increased levels of several key immune response-related proteins, including Stat1, Trem2 and NF-kB, and by activation of astrocytes and microglia in the KO brain. Following treating the KO mice with a selective NF-kB inhibitor, the KO mice exhibited improved behaviors and reduced neuroinflammation compared to the control animals. These data indicate that impaired 26S proteasome causes AD-like cognitive deficiency and induces neuroinflammation mediated largely by NF-kB, which will help develop effective therapeutics and aid to better understand the pathogenesis of AD and many other neurodegenerative disorders where impaired proteasome is consistently coupled with neuroinflammation.

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“…Some drugs and exogenous substances can promote or inhibit the release of exosomes, or change the composition of exosomes, to alleviate the disease or improve symptoms. EVs derived from neural stem cells are produced more abundantly in response to heat shock (HS), and their morphology and cargo are altered to allow improved neuroprotection against oxidative stress and Aβ-induced neurotoxicity [ 111 ]. Exosomes-Mir-21 have successfully reduced neuronal apoptosis, ameliorated neuroinflammation, and increased BBB permeability in the brain at low concentrations.…”

Section: Exosomes In the Diagnosis And Treatment Of Neuropsychiatric ...mentioning

confidence: 99%

Exosomes: potential targets for the diagnosis and treatment of neuropsychiatric disorders

Li,

Yuan,

Xie

et al. 2024

J Transl Med

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The field of neuropsychiatry is considered a middle ground between neurological and psychiatric disorders, thereby bridging the conventional boundaries between matter and mind, consciousness, and function. Neuropsychiatry aims to evaluate and treat cognitive, behavioral, and emotional disorders in individuals with neurological conditions. However, the pathophysiology of these disorders is not yet fully understood, and objective biological indicators for these conditions are currently lacking. Treatment options are also limited due to the blood–brain barrier, which results in poor treatment effects. Additionally, many drugs, particularly antipsychotic drugs, have adverse reactions, which make them difficult to tolerate for patients. As a result, patients often abandon treatment owing to these adverse reactions. Since the discovery of exosomes in 1983, they have been extensively studied in various diseases owing to their potential as nanocellulators for information exchange between cells. Because exosomes can freely travel between the center and periphery, brain-derived exosomes can reflect the state of the brain, which has considerable advantages in diagnosis and treatment. In addition, administration of engineered exosomes can improve therapeutic efficacy, allow lesion targeting, ensure drug stability, and prevent systemic adverse effects. Therefore, this article reviews the source and biological function of exosomes, relationship between exosomes and the blood–brain barrier, relationship between exosomes and the pathological mechanism of neuropsychiatric disorders, exosomes in the diagnosis and treatment of neuropsychiatric disorders, and application of engineered exosomes in neuropsychiatric disorders.

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Heat Shock-Induced Extracellular Vesicles Derived from Neural Stem Cells Confer Marked Neuroprotection Against Oxidative Stress and Amyloid-β-Caused Neurotoxicity

Cited by 16 publications

References 24 publications

Thermotolerance in S. cerevisiae as a model to study extracellular vesicle biology

Thermotolerance in S. cerevisiae as a model to study extracellular vesicle biology

Impaired 26S proteasome causes learning and memory deficiency and induces neuroinflammation mediated by NF-κB in mice

Exosomes: potential targets for the diagnosis and treatment of neuropsychiatric disorders

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