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We used an aging model to study potential spontaneous accumulation of amyloid-\u03b2 (A\u03b2) in HIF-P4H-2-deficient mice and a transgenic APP\/PSEN1 mouse model subjected to prolonged sustained environmental hypoxia (15% O<jats:sub>2<\/jats:sub> for 6\u00a0weeks) at two different time points of the disease; at age of 4 and 10\u00a0months. In both settings, activation of the hypoxia response reduced brain protein aggregate levels and this associated with higher vascularity. In the senescent HIF-P4H-2-deficient mice metabolic reprogramming also contributed to less protein aggregates while in APP\/PSEN1 mice lesser A\u03b2 associated additionally with hypoxia-mediated favorable responses to neuroinflammation and amyloid precursor protein processing. In conclusion, continuous, non-full-scale activation of the HIF pathway appears to mediate protection against neurodegeneration via several mechanisms and should be studied as a treatment option for AD.<\/jats:p>\n                <jats:p><jats:bold>Graphical abstract<\/jats:bold><\/jats:p>","DOI":"10.1007\/s00018-022-04460-6","type":"journal-article","created":{"date-parts":[[2022,7,19]],"date-time":"2022-07-19T13:02:51Z","timestamp":1658235771000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Activation of the hypoxia response protects mice from amyloid-\u03b2 accumulation"],"prefix":"10.1007","volume":"79","author":[{"given":"Teemu","family":"Ollonen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margareta","family":"Kurkela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Laitakari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuli","family":"Sakko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henna","family":"Koivisto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johanna","family":"Myllyharju","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heikki","family":"Tanila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raisa","family":"Serpi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2827-8229","authenticated-orcid":false,"given":"Peppi","family":"Koivunen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,7,19]]},"reference":[{"key":"4460_CR1","doi-asserted-by":"publisher","first-page":"329","DOI":"10.1056\/NEJMra0909142","volume":"362","author":"HW Querfurth","year":"2010","unstructured":"Querfurth HW, LaFerla FM (2010) Alzheimer\u2019s disease. 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