{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T10:14:58Z","timestamp":1772446498861,"version":"3.50.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T00:00:00Z","timestamp":1679011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100014813","name":"Arizona Alzheimer\u2019s Consortium","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100014813","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012807","name":"Midwestern University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100012807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,8,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Alzheimer's disease (AD) is an age-related disorder that results in progressive cognitive impairment and memory loss. Deposition of amyloid \u03b2 (A\u03b2) peptides in senile plaques is a hallmark of AD. \u03b3-secretase produces A\u03b2 peptides, mostly as the soluble A\u03b240 with fewer insoluble A\u03b242 peptides. Rare, early-onset AD (EOAD) occurs in individuals under 60 years of age. Most EOAD cases are due to unknown genetic causes, but a subset is due to mutations in the genes encoding the amyloid precursor protein that is processed into A\u03b2 peptides or the presenilins (PS1 and PS2) that process APP. PS1 interacts with the epsilon isoform of glial fibrillary acidic protein (GFAP\u025b), a protein found in the subventricular zone of the brain. We have found that GFAP\u025b interacts with the telomere protection factor RAP1 (TERF2IP). RAP1 can also interact with PS1 alone or with GFAP\u025b in vitro. Our data show that the nuclear protein RAP1 has an extratelomeric role in the cytoplasm through its interactions with GFAP\u025b and PS1. GFAP\u025b coprecipitated with RAP1 from human cell extracts. RAP1, GFAP\u025b, and PS1 all colocalized in human SH-SY5Y cells. Using a genetic model of the \u03b3-secretase complex in Saccharomyces cerevisiae, RAP1 increased \u03b3-secretase activity, and this was potentiated by GFAP\u025b. Our studies are the first to connect RAP1 with an age-related disorder.<\/jats:p>","DOI":"10.1093\/g3journal\/jkad057","type":"journal-article","created":{"date-parts":[[2023,3,17]],"date-time":"2023-03-17T13:23:21Z","timestamp":1679059401000},"source":"Crossref","is-referenced-by-count":4,"title":["The human RAP1 and GFAP\u025b proteins increase \u03b3-secretase activity in a yeast model system"],"prefix":"10.1093","volume":"13","author":[{"given":"Mark J","family":"Swanson","sequence":"first","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Midwestern University , Glendale, AZ 85308 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelsey N","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Midwestern University , Glendale, AZ 85308 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Carpenter","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences, College of Graduate Studies, Midwestern University , Glendale, AZ 85308 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexis","family":"Whetzel","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Midwestern University , Glendale, AZ 85308 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nancy S","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Genetics, Midwestern University , Glendale, AZ 85308 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2023,3,17]]},"reference":[{"key":"2024022108051520700_jkad057-B1","volume-title":"Methods in Yeast Genetics","author":"Adams","year":"1997"},{"issue":"3","key":"2024022108051520700_jkad057-B2","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.molcel.2007.03.023","article-title":"A RAP1\/TRF2 complex inhibits nonhomologous end-joining at human telomeric DNA ends","volume":"26","author":"Bae","year":"2007","journal-title":"Mol Cell"},{"issue":"4","key":"2024022108051520700_jkad057-B3","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1016\/j.cell.2005.02.001","article-title":"Mitochondria, oxidants, and aging","volume":"120","author":"Balaban","year":"2005","journal-title":"Cell"},{"issue":"4","key":"2024022108051520700_jkad057-B4","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1177\/0891988710383571","article-title":"Genetics of Alzheimer disease","volume":"23","author":"Bekris","year":"2010","journal-title":"J Geriatr Psychiatry Neurol"},{"issue":"6265","key":"2024022108051520700_jkad057-B5","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1126\/science.aab3389","article-title":"Human telomere biology: a contributory and interactive factor in aging, disease risks, and protection","volume":"350","author":"Blackburn","year":"2015","journal-title":"Science"},{"issue":"11","key":"2024022108051520700_jkad057-B6","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1016\/s0891-5849(02)00794-3","article-title":"Lipid peroxidation and protein oxidation in Alzheimer's disease brain: potential causes and consequences involving amyloid beta-peptide-associated free radical oxidative stress","volume":"32","author":"Butterfield","year":"2002","journal-title":"Free Radic Biol Med"},{"issue":"Pt 2","key":"2024022108051520700_jkad057-B7","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1016\/j.brainresbull.2016.04.019","article-title":"Physiological and pathological roles of the \u03b3-secretase complex","volume":"126","author":"Carroll","year":"2016","journal-title":"Brain Res Bull"},{"issue":"6405","key":"2024022108051520700_jkad057-B8","doi-asserted-by":"publisher","first-page":"672","DOI":"10.1038\/360672a0","article-title":"Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production","volume":"360","author":"Citron","year":"1992","journal-title":"Nature"},{"issue":"9","key":"2024022108051520700_jkad057-B9","doi-asserted-by":"publisher","first-page":"1340","DOI":"10.1002\/humu.22117","article-title":"Locus-specific mutation databases for neurodegenerative brain diseases","volume":"33","author":"Cruts","year":"2012","journal-title":"Hum Mutat"},{"issue":"18","key":"2024022108051520700_jkad057-B10","doi-asserted-by":"publisher","first-page":"2100","DOI":"10.1101\/gad.1346005","article-title":"Shelterin: the protein complex that shapes and safeguards human telomeres","volume":"19","author":"de Lange","year":"2005","journal-title":"Genes Dev"},{"issue":"36","key":"2024022108051520700_jkad057-B11","doi-asserted-by":"publisher","first-page":"37311","DOI":"10.1074\/jbc.M406228200","article-title":"Co-expression of nicastrin and presenilin rescues a loss of function mutant of APH-1","volume":"279","author":"Edbauer","year":"2004","journal-title":"J Biol Chem"},{"issue":"5","key":"2024022108051520700_jkad057-B12","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1038\/ncb960","article-title":"Reconstitution of gamma-secretase activity","volume":"5","author":"Edbauer","year":"2003","journal-title":"Nat Cell Biol"},{"issue":"1","key":"2024022108051520700_jkad057-B13","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1074\/jbc.M114.629287","article-title":"Suppressor mutations for presenilin 1 familial Alzheimer disease mutants modulate \u03b3-secretase activities","volume":"291","author":"Futai","year":"2016","journal-title":"J Biol Chem"},{"issue":"19","key":"2024022108051520700_jkad057-B14","doi-asserted-by":"publisher","first-page":"13013","DOI":"10.1074\/jbc.M807653200","article-title":"Nicastrin is dispensable for gamma-secretase protease activity in the presence of specific presenilin mutations","volume":"284","author":"Futai","year":"2009","journal-title":"J Biol Chem"},{"issue":"1","key":"2024022108051520700_jkad057-B15","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1038\/nprot.2007.13","article-title":"High-efficiency yeast transformation using the LiAc\/SS carrier DNA\/PEG method","volume":"2","author":"Gietz","year":"2007","journal-title":"Nat Protoc"},{"issue":"9","key":"2024022108051520700_jkad057-B16","doi-asserted-by":"publisher","first-page":"100024","DOI":"10.1101\/pdb.prot100024","article-title":"Preparing GST-, his-, or MBP-fusion proteins from bacteria","volume":"9","author":"Greenfield","year":"2020","journal-title":"Cold Spring Harb Protoc"},{"issue":"1","key":"2024022108051520700_jkad057-B17","doi-asserted-by":"publisher","first-page":"3","DOI":"10.3233\/JAD-2011-101065","article-title":"The many substrates of presenilin\/\u03b3-secretase","volume":"25","author":"Haapasalo","year":"2011","journal-title":"J Alzheimers Dis"},{"issue":"4","key":"2024022108051520700_jkad057-B18","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/0531-5565(92)90068-b","article-title":"The telomere hypothesis of cellular aging","volume":"27","author":"Harley","year":"1992","journal-title":"Exp Gerontol"},{"issue":"1","key":"2024022108051520700_jkad057-B19","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1093\/jb\/mvy081","article-title":"Specific mutations in presenilin 1 cause conformational changes in \u03b3-secretase to modulate amyloid \u03b2 trimming","volume":"165","author":"Imai","year":"2019","journal-title":"J Biochem"},{"issue":"3","key":"2024022108051520700_jkad057-B20","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1177\/1533317514545825","article-title":"The patterns of inheritance in early-onset dementia: Alzheimer's disease and frontotemporal dementia","volume":"30","author":"Jarmolowicz","year":"2015","journal-title":"Am J Alzheimers Dis Other Demen"},{"issue":"3","key":"2024022108051520700_jkad057-B21","doi-asserted-by":"publisher","first-page":"492","DOI":"10.1016\/j.neurobiolaging.2013.09.035","article-title":"Glial fibrillary acidic protein isoform expression in plaque related astrogliosis in Alzheimer's disease","volume":"35","author":"Kamphuis","year":"2014","journal-title":"Neurobiol Aging"},{"issue":"11","key":"2024022108051520700_jkad057-B22","doi-asserted-by":"publisher","first-page":"6382","DOI":"10.1073\/pnas.1037392100","article-title":"Gamma-secretase is a membrane protein complex comprised of presenilin, nicastrin, Aph-1, and Pen-2","volume":"100","author":"Kimberly","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"3","key":"2024022108051520700_jkad057-B23","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1038\/s41582-018-0132-6","article-title":"Dementia in Down syndrome: unique insights for Alzheimer disease research","volume":"15","author":"Lott","year":"2019","journal-title":"Nat Rev Neurol"},{"issue":"1","key":"2024022108051520700_jkad057-B24","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s13578-021-00738-7","article-title":"Turning the tide on Alzheimer's disease: modulation of \u03b3-secretase","volume":"12","author":"Luo","year":"2022","journal-title":"Cell Biosci"},{"issue":"3","key":"2024022108051520700_jkad057-B25","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1111\/nan.12672","article-title":"Telomeric alterations in the default mode network during the progression of Alzheimer's disease: selective vulnerability of the precuneus","volume":"47","author":"Mahady","year":"2021","journal-title":"Neuropathol Appl Neurobiol"},{"issue":"9","key":"2024022108051520700_jkad057-B26","doi-asserted-by":"publisher","first-page":"429","DOI":"10.4103\/1947-2714.100998","article-title":"Western blot: technique, theory, and trouble shooting","volume":"4","author":"Mahmood","year":"2012","journal-title":"N Am J Med Sci"},{"issue":"15","key":"2024022108051520700_jkad057-B27","doi-asserted-by":"publisher","first-page":"3577","DOI":"10.1093\/nar\/26.15.3577","article-title":"Assessment of aryl hydrocarbon receptor complex interactions using pBEVY plasmids: expressionvectors with bi-directional promoters for use in Saccharomyces cerevisiae","volume":"26","author":"Miller","year":"1998","journal-title":"Nucleic Acids Res"},{"issue":"39","key":"2024022108051520700_jkad057-B28","doi-asserted-by":"publisher","first-page":"23515","DOI":"10.1074\/jbc.R115.677211","article-title":"Amyloid precursor protein (APP) metabolites APP intracellular fragment (AICD), A\u03b242, and tau in nuclear roles","volume":"290","author":"Multhaup","year":"2015","journal-title":"J Biol Chem"},{"issue":"33","key":"2024022108051520700_jkad057-B29","doi-asserted-by":"publisher","first-page":"29983","DOI":"10.1074\/jbc.M112121200","article-title":"A new splice variant of glial fibrillary acidic protein, GFAP epsilon, interacts with the presenilin proteins","volume":"277","author":"Nielsen","year":"2002","journal-title":"J Biol Chem"},{"key":"2024022108051520700_jkad057-B30","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1016\/j.pneurobio.2016.01.001","article-title":"Astrogliosis: an integral player in the pathogenesis of Alzheimer's disease","volume":"144","author":"Osborn","year":"2016","journal-title":"Prog Neurobiol"},{"issue":"1","key":"2024022108051520700_jkad057-B31","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1146\/annurev.genet.41.110306.130350","article-title":"How shelterin protects mammalian telomeres","volume":"42","author":"Palm","year":"2008","journal-title":"Annu Rev Genet"},{"issue":"2","key":"2024022108051520700_jkad057-B32","doi-asserted-by":"publisher","first-page":"171","DOI":"10.3233\/jad-2004-6209","article-title":"Lipid peroxidation and oxidative imbalance: early functional events in Alzheimer's disease","volume":"6","author":"Pratic\u00f2","year":"2004","journal-title":"J Alzheimers Dis"},{"issue":"4","key":"2024022108051520700_jkad057-B33","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1002\/glia.20243","article-title":"Adult human subventricular, subgranular, and subpial zones contain astrocytes with a specialized intermediate filament cytoskeleton","volume":"52","author":"Roelofs","year":"2005","journal-title":"Glia"},{"key":"2024022108051520700_jkad057-B34","volume-title":"Molecular Cloning: A Lab Manual","author":"Sambrook","year":"2001","edition":"3rd ed"},{"issue":"1","key":"2024022108051520700_jkad057-B35","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1038\/35036093","article-title":"Hayflick, his limit, and cellular ageing","volume":"1","author":"Shay","year":"2000","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"17","key":"2024022108051520700_jkad057-B36","doi-asserted-by":"publisher","first-page":"4258","DOI":"10.3390\/ijms20174258","article-title":"Oxidative stress: role and response of short guanine tracts at genomic locations","volume":"20","author":"Singh","year":"2019","journal-title":"Int J Mol Sci"},{"issue":"11","key":"2024022108051520700_jkad057-B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010506","article-title":"Aberrant expression and localization of the RAP1 shelterin protein contribute to age-related phenotypes","volume":"18","author":"Stock","year":"2022","journal-title":"PLoS Genet"},{"issue":"2","key":"2024022108051520700_jkad057-B38","doi-asserted-by":"publisher","first-page":"181","DOI":"10.3892\/br.2016.707","article-title":"Telomere protein RAP1 levels are affected by cellular aging and oxidative stress","volume":"5","author":"Swanson","year":"2016","journal-title":"Biomed Rep"},{"issue":"8","key":"2024022108051520700_jkad057-B39","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1038\/ncb2080","article-title":"Telomere-independent rap1 is an IKK adaptor and regulates NF-kappaB-dependent gene expression","volume":"12","author":"Teo","year":"2010","journal-title":"Nat Cell Biol"},{"issue":"19","key":"2024022108051520700_jkad057-B40","doi-asserted-by":"publisher","first-page":"10315","DOI":"10.1073\/pnas.93.19.10315","article-title":"Reverse two-hybrid and one-hybrid systems to detect dissociation of protein\u2013protein and DNA\u2013protein interactions","volume":"93","author":"Vidal","year":"1996","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"1","key":"2024022108051520700_jkad057-B41","doi-asserted-by":"publisher","first-page":"507","DOI":"10.3390\/ijms23010507","article-title":"Specific mutations in aph1 cause \u03b3-secretase activation","volume":"23","author":"Watanabe","year":"2022","journal-title":"Int J Mol Sci"},{"issue":"2","key":"2024022108051520700_jkad057-B42","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1186\/alzrt107","article-title":"Molecular consequences of amyloid precursor protein and presenilin mutations causing autosomal-dominant Alzheimer's disease","volume":"4","author":"Weggen","year":"2012","journal-title":"Alzheimers Res Ther"},{"key":"2024022108051520700_jkad057-B43","doi-asserted-by":"publisher","first-page":"614690","DOI":"10.3389\/fnagi.2020.614690","article-title":"\u03b3-Secretase modulatory proteins: the guiding hand behind the running scissors","volume":"12","author":"Wong","year":"2020","journal-title":"Front Aging Neurosci"},{"issue":"6","key":"2024022108051520700_jkad057-B44","doi-asserted-by":"publisher","first-page":"364","DOI":"10.1016\/j.tins.2015.04.003","article-title":"Glial fibrillary acidic protein: from intermediate filament assembly and gliosis to neurobiomarker","volume":"38","author":"Yang","year":"2015","journal-title":"Trends Neurosci"},{"issue":"4","key":"2024022108051520700_jkad057-B45","doi-asserted-by":"publisher","first-page":"1751","DOI":"10.1016\/j.bbrc.2016.09.018","article-title":"Specific combinations of presenilins and Aph1s affect the substrate specificity and activity of \u03b3-secretase","volume":"478","author":"Yonemura","year":"2016","journal-title":"Biochem Biophys Res Commun"},{"issue":"52","key":"2024022108051520700_jkad057-B46","doi-asserted-by":"publisher","first-page":"44569","DOI":"10.1074\/jbc.M111.270108","article-title":"Comparison of presenilin 1 and presenilin 2 \u03b3-secretase activities using a yeast reconstitution system","volume":"286","author":"Yonemura","year":"2011","journal-title":"J Biol Chem"},{"issue":"1","key":"2024022108051520700_jkad057-B47","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/1756-6606-4-3","article-title":"APP Processing in Alzheimer's disease","volume":"4","author":"Zhang","year":"2011","journal-title":"Mol Brain"},{"issue":"3","key":"2024022108051520700_jkad057-B48","doi-asserted-by":"publisher","first-page":"38","DOI":"10.3978\/j.issn.2305-5839.2015.01.19","article-title":"Rate of early onset Alzheimer's disease: a systematic review and meta-analysis","volume":"3","author":"Zhu","year":"2015","journal-title":"Ann Transl Med"}],"container-title":["G3: Genes, Genomes, Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/g3journal\/advance-article-pdf\/doi\/10.1093\/g3journal\/jkad057\/49679284\/jkad057.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/g3journal\/article-pdf\/13\/8\/jkad057\/56717683\/jkad057.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/g3journal\/article-pdf\/13\/8\/jkad057\/56717683\/jkad057.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,21]],"date-time":"2024-02-21T08:05:35Z","timestamp":1708502735000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/g3journal\/article\/doi\/10.1093\/g3journal\/jkad057\/7079746"}},"subtitle":[],"editor":[{"given":"P","family":"Hieter","sequence":"additional","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,3,17]]},"references-count":48,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2023,3,17]]},"published-print":{"date-parts":[[2023,8,9]]}},"URL":"https:\/\/doi.org\/10.1093\/g3journal\/jkad057","relation":{},"ISSN":["2160-1836"],"issn-type":[{"value":"2160-1836","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2023,8]]},"published":{"date-parts":[[2023,3,17]]},"article-number":"jkad057"}}