{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T01:32:30Z","timestamp":1787880750423,"version":"build-2784847793"},"reference-count":41,"publisher":"National Academy of Sciences","issue":"42","license":[{"start":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T00:00:00Z","timestamp":1696896000000},"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":[[2023,10,17]]},"abstract":"<jats:p>\n                    Mutations in the\n                    <jats:italic>Presenilin<\/jats:italic>\n                    (\n                    <jats:italic>PSEN1<\/jats:italic>\n                    and\n                    <jats:italic>PSEN2<\/jats:italic>\n                    ) genes are the major cause of early-onset familial Alzheimer\u2019s disease (FAD). Presenilin (PS) is the catalytic subunit of the \u03b3-secretase complex, which cleaves type I transmembrane proteins, such as Notch and the amyloid precursor protein (APP), and plays an evolutionarily conserved role in the protection of neuronal survival during aging. FAD\n                    <jats:italic>PSEN1<\/jats:italic>\n                    mutations exhibit impaired \u03b3-secretase activity in cell culture, in vitro, and knockin (KI) mouse brains, and the L435F mutation is the most severe in reducing \u03b3-secretase activity and is located closest to the active site of \u03b3-secretase. Here, we report that introduction of the codon-optimized wild-type human\n                    <jats:italic>PSEN1<\/jats:italic>\n                    cDNA by adeno-associated virus 9 (AAV9) results in broadly distributed, sustained, low to moderate levels of human PS1 (hPS1) expression and rescues impaired \u03b3-secretase activity in the cerebral cortex of\n                    <jats:italic>Psen<\/jats:italic>\n                    mutant mice either lacking PS or expressing the\n                    <jats:italic>Psen1<\/jats:italic>\n                    L435F KI allele, as evaluated by endogenous \u03b3-secretase substrates of APP and recombinant \u03b3-secretase products of Notch intracellular domain and A\u03b2 peptides. Furthermore, introduction of hPS1 by AAV9 alleviates impairments of synaptic plasticity and learning and memory in\n                    <jats:italic>Psen<\/jats:italic>\n                    mutant mice. Importantly, AAV9 delivery of hPS1 ameliorates neurodegeneration in the cerebral cortex of aged\n                    <jats:italic>Psen<\/jats:italic>\n                    mutant mice, as shown by the reversal of age-dependent loss of cortical neurons and elevated microgliosis and astrogliosis. These results together show that moderate hPS1 expression by AAV9 is sufficient to rescue impaired \u03b3-secretase activity, synaptic and memory deficits, and neurodegeneration caused by\n                    <jats:italic>Psen<\/jats:italic>\n                    mutations in mouse models.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2306714120","type":"journal-article","created":{"date-parts":[[2023,10,10]],"date-time":"2023-10-10T13:42:03Z","timestamp":1696945323000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":12,"title":["Human Presenilin-1 delivered by AAV9 rescues impaired \u03b3-secretase activity, memory deficits, and neurodegeneration in\n                    <i>Psen<\/i>\n                    mutant mice"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7521-1206","authenticated-orcid":false,"given":"Paola","family":"Montenegro","sequence":"first","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phoenix","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0259-110X","authenticated-orcid":false,"given":"Jongkyun","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0020-4631","authenticated-orcid":false,"given":"Sang Hun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4467-9326","authenticated-orcid":false,"given":"Sofia","family":"Leone","sequence":"additional","affiliation":[{"name":"Department of Neurology, Brigham and Women\u2019s Hospital, 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, Boston, MA 02115"},{"name":"Program in Neuroscience, Harvard Medical School, Boston, MA 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