{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T14:02:20Z","timestamp":1788876140978,"version":"build-2803163510"},"reference-count":44,"publisher":"National Academy of Sciences","issue":"34","license":[{"start":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T00:00:00Z","timestamp":1723507200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R01NS041783"],"award-info":[{"award-number":["R01NS041783"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["RF1AG063520"],"award-info":[{"award-number":["RF1AG063520"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2024,8,20]]},"abstract":"<jats:p>\n                    Mutations in the\n                    <jats:italic>PSEN<\/jats:italic>\n                    genes are the major cause of familial Alzheimer\u2019s disease, and presenilin (PS) is the catalytic subunit of \u03b3-secretase, which cleaves type I transmembrane proteins, including the amyloid precursor protein (APP) to release A\u03b2 peptides. While PS plays an essential role in the protection of neuronal survival,\n                    <jats:italic>PSEN<\/jats:italic>\n                    mutations also increase the ratio of A\u03b242\/A\u03b240. Thus, it remains unresolved whether\n                    <jats:italic>PSEN<\/jats:italic>\n                    mutations cause AD via a loss of its essential function or increases of A\u03b242\/A\u03b240. Here, we test whether the knockin (KI) allele of\n                    <jats:italic>Psen1<\/jats:italic>\n                    L435F, the most severe FAD mutation located closest to the active site of \u03b3-secretase, causes age-dependent cortical neurodegeneration independent of A\u03b2 by crossing various\n                    <jats:italic>Psen<\/jats:italic>\n                    mutant mice to the\n                    <jats:italic>App<\/jats:italic>\n                    -null background. We report that removing A\u03b2 completely through APP deficiency has no impact on the age-dependent neurodegeneration in\n                    <jats:italic>Psen<\/jats:italic>\n                    mutant mice, as shown by the absence of effects on the reduced cortical volume and decreases of cortical neurons at the ages of 12 and 18 mo. The L435F KI allele increases A\u03b242\/A\u03b240 in the cerebral cortex while decreasing de novo production and steady-state levels of A\u03b242 and A\u03b240 in the presence of APP. Furthermore, APP deficiency does not alleviate elevated apoptotic cell death in the cerebral cortex of\n                    <jats:italic>Psen<\/jats:italic>\n                    mutant mice at the ages of 2, 12, and 18 mo, nor does it affect the progressive microgliosis in these mice. Our findings demonstrate that\n                    <jats:italic>Psen1<\/jats:italic>\n                    mutations cause age-dependent neurodegeneration independent of A\u03b2, providing further support for a loss-of-function pathogenic mechanism underlying\n                    <jats:italic>PSEN<\/jats:italic>\n                    mutations.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2409343121","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T11:32:11Z","timestamp":1723548731000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":16,"title":["Cortical neurodegeneration caused by\n                    <i>Psen1<\/i>\n                    mutations is independent of A\u03b2"],"prefix":"10.1073","volume":"121","author":[{"given":"Kuo","family":"Yan","sequence":"first","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jongkyun","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-1206","authenticated-orcid":false,"given":"Paola","family":"Montenegro","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1160-7118","authenticated-orcid":false,"given":"Jie","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Harvard Medical School, Boston, MA 02115"},{"name":"Program in Neuroscience, Harvard Medical School, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/375754a0"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/376775a0"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1038\/34910"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/19083"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.12.6959"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/349704a0"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1038\/383710a0"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm0896-864"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.1072994"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(04)00182-5"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0402733101"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409544200"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0010195"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0317-12.2012"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-020-00419-y"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0896-6273(01)00417-2"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature08177"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2010.07011.x"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1304171110"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-017-0189-5"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-021-00796-5"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-023-01009-x"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0608332104"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.116962"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0954-13.2013"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.02.010"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.03.009"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2306714120"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1618657114"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1713605114"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2013.10.018"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.03.010"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3261-14.2014"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1534\/genetics.116.196881"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/iyad202"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0006-291X(84)80190-4"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1016\/0006-291X(84)91209-9"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410300410"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-199709000-00002"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2020.08.011"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature14892"},{"key":"e_1_3_4_42_2","article-title":"Alzheimer\u2019s disease drug development pipeline: 2020","volume":"6","author":"Cummings J.","year":"2020","unstructured":"J. Cummings, G. Lee, A. Ritter, M. Sabbagh, K. Zhong, Alzheimer\u2019s disease drug development pipeline: 2020. Alzheimers Dement. 6, e12050 (2020).","journal-title":"Alzheimers Dement."},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.100654"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2409343121","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T11:34:21Z","timestamp":1723548861000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2409343121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,13]]},"references-count":44,"journal-issue":{"issue":"34","published-print":{"date-parts":[[2024,8,20]]}},"alternative-id":["10.1073\/pnas.2409343121"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2409343121","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,13]]},"assertion":[{"value":"2024-06-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-07-16","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-08-13","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2409343121"}}