{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T23:15:18Z","timestamp":1793142918980,"version":"4.5.0"},"reference-count":68,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T00:00:00Z","timestamp":1725580800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Canadian Institutes of Health Research Institute of Neurosciences, Mental Health and Addiction","award":["PJT165947"],"award-info":[{"award-number":["PJT165947"]}]},{"name":"Ecole Polytechnique Commemorative Award from the Canadian Federation of University Women"},{"name":"Natural Sciences and Engineering Research Council of Canada Post-Graduate Scholarships \u2013 Doctoral"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Mutations in the presenilin (\n                    <jats:italic>PS<\/jats:italic>\n                    ) genes are a predominant cause of familial Alzheimer\u2019s disease (fAD). An ortholog of\n                    <jats:italic>PS<\/jats:italic>\n                    in the genetic model organism\n                    <jats:italic>Caenorhabditis elegans (C<\/jats:italic>\n                    .\n                    <jats:italic>elegans)<\/jats:italic>\n                    is\n                    <jats:italic>sel-12<\/jats:italic>\n                    . Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (A\u03b2), however this hypothesis has been challenged by recent evidence. As\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    lack amyloid beta (A\u03b2), the goal of this work was to examine A\u03b2-independent effects of mutations in\n                    <jats:italic>sel-12<\/jats:italic>\n                    and\n                    <jats:italic>PS1\/PS2<\/jats:italic>\n                    on behaviour and sensory neuron morphology across the lifespan in a\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    model. Olfactory chemotaxis experiments were conducted on\n                    <jats:italic>sel-12<\/jats:italic>\n                    (\n                    <jats:italic>ok2078<\/jats:italic>\n                    ) loss-of-function mutant worms. Adult\n                    <jats:italic>sel-12<\/jats:italic>\n                    mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype in\n                    <jats:italic>sel-12<\/jats:italic>\n                    mutant worms is rescued by transgenic over-expression of human wild-type\n                    <jats:italic>PS1<\/jats:italic>\n                    , but not the classic fAD-associated variant\n                    <jats:italic>PS1<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>C410Y<\/jats:italic>\n                    <\/jats:sub>\n                    , when expression was driven by either the endogenous\n                    <jats:italic>sel-12<\/jats:italic>\n                    promoter (\n                    <jats:italic>Psel-12)<\/jats:italic>\n                    , a pan-neuronal promoter (\n                    <jats:italic>Primb-1<\/jats:italic>\n                    ), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (\n                    <jats:italic>Psra-6<\/jats:italic>\n                    ,\n                    <jats:italic>Podr-10<\/jats:italic>\n                    ). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation in\n                    <jats:italic>PS1<\/jats:italic>\n                    (\n                    <jats:italic>PS1<\/jats:italic>\n                    <jats:sub>\n                      <jats:italic>\u0394S169<\/jats:italic>\n                    <\/jats:sub>\n                    ) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time in\n                    <jats:italic>sel-12<\/jats:italic>\n                    mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an A\u03b2-independent neurodegeneration in\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    that was rescued by cell specific over-expression of wild-type human presenilin.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0289435","type":"journal-article","created":{"date-parts":[[2024,9,6]],"date-time":"2024-09-06T13:52:48Z","timestamp":1725630768000},"page":"e0289435","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":5,"title":["A familial Alzheimer\u2019s disease associated mutation in presenilin-1 mediates amyloid-beta independent cell specific neurodegeneration"],"prefix":"10.1371","volume":"19","author":[{"given":"Mahraz","family":"Parvand","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0630-2769","authenticated-orcid":true,"given":"Joseph J. H.","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tahereh","family":"Bozorgmehr","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawson","family":"Born","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvaro","family":"Luna Cortes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1781-0654","authenticated-orcid":true,"given":"Catharine H.","family":"Rankin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,9,6]]},"reference":[{"key":"pone.0289435.ref001","doi-asserted-by":"crossref","first-page":"111","DOI":"10.31887\/DCNS.2009.11.2\/cqiu","article-title":"Epidemiology of Alzheimer\u2019s disease: Occurrence, determinants, and strategies toward intervention","volume":"11","author":"C Qiu","year":"2009","journal-title":"Dialogues in Clinical Neuroscience"},{"issue":"9","key":"pone.0289435.ref002","doi-asserted-by":"crossref","first-page":"851","DOI":"10.1212\/WNL.0000000000000733","article-title":"Recommendations of the alzheimer\u2019s disease-related dementias conference","volume":"83","author":"TJ Montine","year":"2014","journal-title":"Neurology"},{"key":"pone.0289435.ref003","doi-asserted-by":"crossref","first-page":"291","DOI":"10.3233\/JAD-143006","article-title":"Biomarkers in Sporadic and Familial Alzheimer\u2019s Disease","volume":"47","author":"S Lista","year":"2015","journal-title":"Journal of Alzheimer\u2019s Disease"},{"key":"pone.0289435.ref004","first-page":"79","article-title":"The genetics of Alzheimer\u2019s disease","author":"L Bertram","year":"2012","journal-title":"In: Progress in Molecular Biology and Translational Science"},{"issue":"9","key":"pone.0289435.ref005","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1056\/NEJMoa1202753","article-title":"Clinical and Biomarker Changes in Dominantly Inherited Alzheimer\u2019s Disease","volume":"367","author":"RJ Bateman","year":"2012","journal-title":"N Engl J Med"},{"issue":"1","key":"pone.0289435.ref006","doi-asserted-by":"crossref","first-page":"a006304","DOI":"10.1101\/cshperspect.a006304","article-title":"Presenilins and \u03b3-secretase: Structure, function, and role in Alzheimer disease","volume":"2","author":"B De Strooper","year":"2012","journal-title":"Cold Spring Harb Perspect Med"},{"key":"pone.0289435.ref007","unstructured":"Alzforum. 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