{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:19:26Z","timestamp":1793042366590,"version":"4.5.0"},"reference-count":183,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T00:00:00Z","timestamp":1692921600000},"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. Aging Neurosci."],"abstract":"<jats:p>\n                    Aldehyde dehydrogenase 2 (ALDH2) is a mitochondrial enzyme that reduces cell injuries via detoxification of lipid-peroxidation product, 4-hydroxy-2-nonenal (hydroxynonenal). It is generated exogenously via deep-frying of linoleic acid-rich cooking oils and\/or endogenously via oxidation of fatty acids involved in biomembranes. Although its toxicity for human health is widely accepted, the underlying mechanism long remained unknown. In 1998, Yamashima et al. have formulated the \u201c\n                    <jats:italic>calpain\u2013cathepsin hypothesis<\/jats:italic>\n                    \u201d as a molecular mechanism of ischemic neuronal death. Subsequently, they found that calpain cleaves Hsp70.1 which became vulnerable after the hydroxynonenal-induced carbonylation at the key site Arg469. Since it is the pivotal aberration that induces lysosomal membrane rupture, they suggested that neuronal death in Alzheimer\u2019s disease similarly occurs by chronic ischemia via the calpain\u2013cathepsin cascade triggered by hydroxynonenal. For nearly three decades, amyloid \u03b2 (A\u03b2) peptide was thought to be a root substance of Alzheimer\u2019s disease. However, because of both the insignificant correlations between A\u03b2 depositions and occurrence of neuronal death or dementia, and the negative results of anti-A\u03b2 medicines tested so far in the patients with Alzheimer\u2019s disease, the strength of the \u201c\n                    <jats:italic>amyloid cascade hypothesis<\/jats:italic>\n                    \u201d has been weakened. Recent works have suggested that hydroxynonenal is a mediator of programmed cell death not only in the brain, but also in the liver, pancreas, heart, etc. Increment of hydroxynonenal was considered an early event in the development of Alzheimer\u2019s disease. This review aims at suggesting ways out of the tunnel, focusing on the implication of hydroxynonenal in this disease. Herein, the mechanism of Alzheimer neuronal death is discussed by focusing on Hsp70.1 with a dual function as chaperone protein and lysosomal stabilizer. We suggest that A\u03b2 is not a culprit of Alzheimer\u2019s disease, but merely a byproduct of autophagy\/lysosomal failure resulting from hydroxynonenal-induced Hsp70.1 disorder. Enhancing ALDH2 activity to detoxify hydroxynonenal emerges as a promising strategy for preventing and treating Alzheimer\u2019s disease.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2023.1211141","type":"journal-article","created":{"date-parts":[[2023,8,25]],"date-time":"2023-08-25T14:46:42Z","timestamp":1692974802000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["Implication of the cooking oil-peroxidation product \u201chydroxynonenal\u201d for Alzheimer\u2019s disease"],"prefix":"10.3389","volume":"15","author":[{"given":"Tetsumori","family":"Yamashima","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuya","family":"Seike","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daria","family":"Mochly-Rosen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Che-Hong","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mitsuru","family":"Kikuchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eishiro","family":"Mizukoshi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,8,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2021.147342","article-title":"History in perspective: How Alzheimer\u2019s disease came to be where it is?","volume":"1758","author":"Ahmed","year":"2021","journal-title":"Brain Res"},{"key":"B2","doi-asserted-by":"publisher","first-page":"1509","DOI":"10.1001\/archneur.65.11.1509","article-title":"Frequent amyloid deposition without significant cognitive impairment among the elderly.","volume":"65","author":"Aizenstein","year":"2008","journal-title":"Arch. 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