{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:15:27Z","timestamp":1788257727343,"version":"build-2803163510"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Chronic vascular exposure to elevated levels of lipoprotein-amyloid-\u03b2 (A\u03b2) contributes to blood\u2013brain barrier (BBB) disruption and the pathogenesis of Alzheimer\u2019s disease (AD). Therapeutic agents such as probucol have been shown to reduce circulating lipoprotein-A\u03b2 levels and mitigate neurovascular dysfunction and cognitive decline. Type 2 diabetes (T2D) impairs BBB integrity and is characterised by dyslipidaemia and metabolic disturbances that may influence the peripheral metabolism of lipoprotein-A\u03b2. However, the effects of diabetes on lipoprotein-A\u03b2 homeostasis and neurovascular integrity remain poorly understood. This study investigated whether diabetes impairs lipoprotein and A\u03b2 metabolism and whether treatment with HA1, a probucol analogue with improved bioavailability, or APOC3 siRNA can modify these metabolic changes and improve neurovascular and behavioural outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Non-diabetic db\/+ mice, untreated diabetic db\/db mice, and diabetic db\/db mice treated with HA1 or APOC3 siRNA were used to determine how diabetes and therapeutic modulation of lipoprotein metabolism affect circulating A\u03b2, neurovascular integrity, and behavioural outcomes. Total plasma A\u03b2 and ApoB levels were measured by ELISA. Intestinal A\u03b2 and ApoB, neurovascular integrity, neuroinflammation, and oxidative stress were assessed by immunofluorescence. Anxiety-like behaviour and short- and long-term memory were evaluated using the open field, novel object recognition, and passive avoidance tests<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Diabetic db\/db mice exhibited increased intestinal A\u03b2 and ApoB immunoreactivity and elevated total plasma A\u03b2\n                      <jats:sub>42<\/jats:sub>\n                      , A\u03b2 oligomer and ApoB, accompanied by heightened BBB permeability and anxiety-like phenotype. HA1 reduced intestinal A\u03b2 and lowered plasma A\u03b2\n                      <jats:sub>42<\/jats:sub>\n                      and A\u03b2 oligomer, prevented IgG extravasation, and improved anxiety. APOC3 siRNA lowered plasma ApoB and plasma A\u03b2\n                      <jats:sub>42<\/jats:sub>\n                      and attenuated neuroinflammation, but did not reduce IgG extravasation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Dysregulated lipoprotein and A\u03b2 metabolism are associated with neurovascular dysfunction and anxiety-like behaviour in diabetes. HA1 shows therapeutic potential by modulating A\u03b2 metabolism and improving neurovascular and behavioural outcomes.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1826957","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:37:02Z","timestamp":1788255422000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Effects of HA1, a probucol analogue, and APOC3 siRNA on lipoprotein and amyloid-\u03b2 metabolism and neurovascular dysfunction in type 2 diabetic mice"],"prefix":"10.3389","volume":"17","author":[{"given":"Arazu","family":"Sharif","sequence":"first","affiliation":[{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]},{"name":"Perron Institute for Neurological and Translational Research","place":["Perth, WA, Australia"]},{"name":"Curtin Medical School, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John Charles Louis","family":"Mamo","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]},{"name":"Perron Institute for Neurological and Translational Research","place":["Perth, WA, Australia"]},{"name":"School of Public Health, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Lam","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]},{"name":"Perron Institute for Neurological and Translational Research","place":["Perth, WA, Australia"]},{"name":"School of Public Health, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Luna","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]},{"name":"Curtin Medical School, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerald F.","family":"Watts","sequence":"additional","affiliation":[{"name":"School of Medicine, University of Western Australia","place":["Perth, WA, Australia"]},{"name":"Department of Cardiology, Royal Perth Hospital","place":["Perth, WA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael Leo","family":"Nesbit","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hani","family":"Al-Salami","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]},{"name":"Curtin Medical School, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Mooranian","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]},{"name":"Curtin Medical School, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryusuke","family":"Takechi","sequence":"additional","affiliation":[{"name":"Curtin Medical Research Institute, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]},{"name":"Perron Institute for Neurological and Translational Research","place":["Perth, WA, Australia"]},{"name":"School of Public Health, Faculty of Health Sciences, Curtin University","place":["Perth, WA, Australia"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"4710","DOI":"10.1021\/JM5002524","article-title":"Structural insights into the molecular mechanism of vitamin D receptor activation by lithocholic acid involving a new mode of ligand recognition","volume":"57","author":"Belorusova","year":"2014","journal-title":"J. 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