{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T10:18:14Z","timestamp":1788257894791,"version":"build-2803163510"},"reference-count":26,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education of Russia","award":["075-15-2024-638"],"award-info":[{"award-number":["075-15-2024-638"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Hypoxia-inducible factors (HIF-1\u03b1, HIF-2\u03b1, HIF-3\u03b1) regulate cellular adaptation to oxygen deprivation, but their region-specific roles in Alzheimer\u2019s disease (AD) and AD with cerebral amyloid angiopathy (CAA) remain unclear. Using post-mortem human brain tissue from aging, AD, and AD + CAA groups, we measured all three HIF isoforms in hippocampal subfields (CA1, CA2, CA4, dentate gyrus) and anterior cingulate cortex (ACC) layers 3 and 5. In the AD hippocampus, two distinct patterns emerged: ischemia-resistant regions (CA4, DG) maintained HIF-2\u03b1 and showed relative resilience, whereas vulnerable regions (CA1, CA2) exhibited HIF-1\u03b1 upregulation, HIF-3\u03b1 loss, and HIF-2\u03b1 dysregulation. The ACC contrasts sharply with the hippocampus by preserving coordinated HIF-1\u03b1\/HIF-3\u03b1 regulation during aging and AD, with layer-specific divergence (exhaustion in layer 3 vs. resilience in layer 5) emerging only upon addition of CAA. Notably, HIF-2\u03b1 in ACC neurons remains stably elevated across all conditions. Taken together, our results highlight HIF-2\u03b1 as a potential contributor to regional vulnerability and raise the possibility that maintaining HIF-2\u03b1 levels, in addition to or instead of modulating HIF-1\u03b1, could be worthy of further investigation in the context of AD and related vascular changes.<\/jats:p>","DOI":"10.3390\/ijms27177784","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T09:48:36Z","timestamp":1788256116000},"page":"7784","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HIF-2\u03b1 Depletion and HIF-1\u03b1 Overexpression in Vulnerable Brain Regions Distinguish Alzheimer\u2019s Disease with Cerebral Amyloid Angiopathy"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0552-6939","authenticated-orcid":false,"given":"Vladimir S.","family":"Sukhorukov","sequence":"first","affiliation":[{"name":"Russian Center of Neurology and Neurosciences, Laboratory of Neuromorphology, 125367 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"resources","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"funding-acquisition","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8999-9986","authenticated-orcid":false,"given":"Tatiana I.","family":"Baranich","sequence":"additional","affiliation":[{"name":"Russian Center of Neurology and Neurosciences, Laboratory of Neuromorphology, 125367 Moscow, Russia"},{"name":"Department of Anatomy and Histology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 125009 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"conceptualization","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-0223-7335","authenticated-orcid":false,"given":"Olga V.","family":"Velts","sequence":"additional","affiliation":[{"name":"Russian Center of Neurology and Neurosciences, Laboratory of Neuromorphology, 125367 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"investigation","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"given":"Kseniia M.","family":"Okulova","sequence":"additional","affiliation":[{"name":"Russian Center of Neurology and Neurosciences, Laboratory of Neuromorphology, 125367 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"validation","vocabulary":"credit"},{"role":"visualization","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5222-5322","authenticated-orcid":false,"given":"Dmitry N.","family":"Voronkov","sequence":"additional","affiliation":[{"name":"Russian Center of Neurology and Neurosciences, Laboratory of Neuromorphology, 125367 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"software","vocabulary":"credit"}]},{"given":"Ekaterina V.","family":"Shcherbak","sequence":"additional","affiliation":[{"name":"Pirogov City Clinical Hospital No. 1, 119049 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"formal-analysis","vocabulary":"credit"},{"role":"data-curation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7112-2556","authenticated-orcid":false,"given":"Anna V.","family":"Egorova","sequence":"additional","affiliation":[{"name":"Russian Center of Neurology and Neurosciences, Laboratory of Neuromorphology, 125367 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"given":"Natalia M.","family":"Mudzhiri","sequence":"additional","affiliation":[{"name":"Russian Center of Neurology and Neurosciences, Laboratory of Neuromorphology, 125367 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"data-curation","vocabulary":"credit"}]},{"given":"Dmitry S.","family":"Lazarev","sequence":"additional","affiliation":[{"name":"Russian Center of Neurology and Neurosciences, Laboratory of Neuromorphology, 125367 Moscow, Russia"},{"name":"Department of Pathology, Pirogov Russian National Research Medical University, 117513 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"visualization","vocabulary":"credit"},{"role":"validation","vocabulary":"credit"}]},{"given":"Alexander P.","family":"Raksha","sequence":"additional","affiliation":[{"name":"Pirogov City Clinical Hospital No. 1, 119049 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"},{"role":"methodology","vocabulary":"credit"}]},{"given":"Alexander N.","family":"Yatskovskiy","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Histology, I.M. 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