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Recent meta-analysis demonstrated the potential link between ALDH2*2 mutation and Alzheimer\u2019s Disease (AD). Other studies have linked chronic alcohol consumption as a risk factor for AD. In the present study, we show that fibroblasts of an AD patient that also has an ALDH2*2 mutation or overexpression of ALDH2*2 in fibroblasts derived from AD patients harboring ApoE \u03b54 allele exhibited increased aldehydic load, oxidative stress, and increased mitochondrial dysfunction relative to healthy subjects and exposure to ethanol exacerbated these dysfunctions. In an in vivo model, daily exposure of WT mice to ethanol for 11\u2009weeks resulted in mitochondrial dysfunction, oxidative stress and increased aldehyde levels in their brains and these pathologies were greater in ALDH2*2\/*2 (homozygous) mice. Following chronic ethanol exposure, the levels of the AD-associated protein, amyloid-\u03b2, and neuroinflammation were higher in the brains of the ALDH2*2\/*2 mice relative to WT. Cultured primary cortical neurons of ALDH2*2\/*2 mice showed increased sensitivity to ethanol and there was a greater activation of their primary astrocytes relative to the responses of neurons or astrocytes from the WT mice. Importantly, an activator of ALDH2 and ALDH2*2, Alda-1, blunted the ethanol-induced increases in A\u03b2, and the neuroinflammation in vitro and in vivo. These data indicate that impairment in the metabolism of aldehydes, and specifically ethanol-derived acetaldehyde, is a contributor to AD associated pathology and highlights the likely risk of alcohol consumption in the general population and especially in East Asians that carry ALDH2*2 mutation.<\/jats:p>","DOI":"10.1186\/s40478-019-0839-7","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T00:07:50Z","timestamp":1576109270000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["Aldehyde dehydrogenase 2 activity and aldehydic load contribute to neuroinflammation and Alzheimer\u2019s disease related pathology"],"prefix":"10.1186","volume":"7","author":[{"given":"Amit U.","family":"Joshi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren D.","family":"Van Wassenhove","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey R.","family":"Logas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paras S.","family":"Minhas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrin I.","family":"Andreasson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth I.","family":"Weinberg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che-Hong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6691-8733","authenticated-orcid":false,"given":"Daria","family":"Mochly-Rosen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,12,12]]},"reference":[{"key":"839_CR1","doi-asserted-by":"publisher","first-page":"1802","DOI":"10.1111\/acer.13168","volume":"40","author":"L Adermark","year":"2016","unstructured":"Adermark L, Bowers MS (2016) Disentangling the Role of Astrocytes in Alcohol Use Disorder. 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