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To understand how peripherally misfolded proteins influence brain functionality, exosomes were isolated from CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      and Ntg mouse blood and were used to treat wild-type (WT) mice and primary cortical neuron-glia mix cultures. Additionally, isolated protein aggregates from the brain following I\/R were isolated and subjected to mass-spectrometric analysis to assess whether the aggregates contained the mutant protein, CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      . To determine whether the CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      misfolding can self-propagate, a misfolded protein seeding assay was performed in cell cultures.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Our results showed that CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      mice exhibited dramatically increased infarct volume, delayed brain functional recovery, and enhanced neuroinflammation and protein aggregation in the brain following I\/R when compared to the Ntg mice. Intriguingly, mass-spectrometric analysis of the protein aggregates isolated from CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      mouse brains confirmed presence of the mutant CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      protein in the brain. Importantly, intravenous administration of WT mice with the exosomes isolated from CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      mouse blood exacerbated I\/R-induced cerebral injury in WT mice. Moreover, incubation of the CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      mouse exosomes with primary neuronal cultures induced pronounced protein aggregation. Transduction of CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      aggregate seeds into cell cultures caused normal CryAB proteins to undergo dramatic aggregation and form large aggregates, suggesting self-propagation of CryAB\n                      <jats:sup>R120G<\/jats:sup>\n                      misfolding in cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These results suggest that peripherally misfolded proteins in the heart remotely enhance neuroinflammation and exacerbate brain injury following I\/R likely through exosomes, which may represent an underappreciated mechanism underlying heart-brain crosstalk.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12974-021-02081-7","type":"journal-article","created":{"date-parts":[[2021,1,20]],"date-time":"2021-01-20T09:03:15Z","timestamp":1611133395000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Peripherally misfolded proteins exacerbate ischemic stroke-induced neuroinflammation and brain injury"],"prefix":"10.1186","volume":"18","author":[{"given":"Yanying","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kalpana","family":"Subedi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aravind","family":"Baride","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svetlana","family":"Romanova","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Callegari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa C.","family":"Huber","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuejun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0392-4458","authenticated-orcid":false,"given":"Hongmin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,1,20]]},"reference":[{"key":"2081_CR1","doi-asserted-by":"publisher","first-page":"a004374","DOI":"10.1101\/cshperspect.a004374","volume":"3","author":"B Chen","year":"2011","unstructured":"Chen B, Retzlaff M, Roos T, Frydman J. 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