{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T19:48:31Z","timestamp":1781898511936,"version":"3.54.5"},"reference-count":86,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T00:00:00Z","timestamp":1616112000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Neuropathological lesions in Alzheimer\u2019s disease (AD) include amyloid plaques formed by the accumulation of amyloid peptides, neurofibrillary tangles made of hyperphosphorylated tau protein, synaptic and neuronal degenerations, and neuroinflammation. The cause of AD is unknown, but according to the amyloid hypothesis, amyloid oligomers could lead to the activation of kinases such as eukaryotic translation initiation factor 2-alpha kinase 2 (PKR), p38, and receptor-interacting serine\/threonine-protein kinase 1 (RIPK1), which all belong to the same stress-activated pathway. Many toxic kinase activations have been described in AD patients and in experimental models. A p38 mitogen-activated protein kinase inhibitor was recently tested in clinical trials but with unsuccessful results. The complex PKR\/P38\/RIPK1 (PKR\/dual specificity mitogen-activated protein kinase kinase 6 (MKK6)\/P38\/MAP kinase-activated protein kinase 2 (MK2)\/RIPK1) is highly activated in AD brains and in the brains of AD transgenic animals. To delineate the implication of this pathway in AD, we carried out a search on PubMed including PKR\/MKK6\/p38\/MK2\/RIPK1, Alzheimer, and therapeutics. The involvement of this signaling pathway in the genesis of AD lesions, including A\u03b2 accumulations and tau phosphorylation as well as cognitive decline, is demonstrated by the reports described in this review. A future combination strategy with kinase inhibitors should be envisaged to modulate the consequences for neurons and other brain cells linked to the abnormal activation of this pathway.<\/jats:p>","DOI":"10.3390\/ijms22063136","type":"journal-article","created":{"date-parts":[[2021,3,19]],"date-time":"2021-03-19T11:18:38Z","timestamp":1616152718000},"page":"3136","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["The PKR\/P38\/RIPK1 Signaling Pathway as a Therapeutic Target in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1848-8628","authenticated-orcid":false,"given":"Jacques","family":"Hugon","sequence":"first","affiliation":[{"name":"Center of Cognitive Neurology, Lariboisiere FW Hospital, University of Paris, AP-HP, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire","family":"Paquet","sequence":"additional","affiliation":[{"name":"Center of Cognitive Neurology, Lariboisiere FW Hospital, University of Paris, AP-HP, 75010 Paris, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0140-6736(15)01124-1","article-title":"Alzheimer\u2019s disease","volume":"388","author":"Scheltens","year":"2016","journal-title":"Lancet"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1007\/s00401-009-0532-1","article-title":"Classification and basic pathology of Alzheimer disease","volume":"118","author":"Duyckaerts","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"EMBO Mol. 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