{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,25]],"date-time":"2026-07-25T12:14:59Z","timestamp":1784981699932,"version":"3.55.0"},"reference-count":57,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T00:00:00Z","timestamp":1715731200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG055523"],"award-info":[{"award-number":["R01AG055523"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG061151"],"award-info":[{"award-number":["R01AG061151"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01AG070154"],"award-info":[{"award-number":["R01AG070154"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Annals of Neurology"],"published-print":{"date-parts":[[2024,8]]},"abstract":"<jats:sec><jats:title>Objectives<\/jats:title><jats:p>Due to increased gene dose for the amyloid precursor protein (APP), elderly adults with Down syndrome (DS) are at a markedly increased risk of Alzheimer's disease (AD), known as DS\u2010AD. How the increased APP gene dose acts and which APP products are responsible for DS\u2010AD is not well understood, thus limiting strategies to target pathogenesis. As one approach to address this question, we used a novel class of \u03b3\u2010secretase modulators that promote \u03b3\u2010site cleavages by the \u03b3\u2010secretase complex, resulting in lower levels of the A\u03b242 and A\u03b240 peptides.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Ts65Dn mice, which serve as a model of DS, were treated via oral gavage with 10\u2009mg\/kg\/weekday of BPN15606 (a potent and novel pyridazine\u2010containing \u03b3\u2010secretase modulators). Treatment started at 3\u2009months\u2010of\u2010age and lasted for 4\u2009months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Demonstrating successful target engagement, treatment with BPN15606 significantly decreased levels of A\u03b240 and A\u03b242 in the cortex and hippocampus; it had no effect on full\u2010length APP or its C\u2010terminal fragments in either 2\u2009N or Ts65Dn mice. Importantly, the levels of total amyloid\u2010\u03b2 were not impacted, pointing to BPN15606\u2010mediated enhancement of processivity of \u03b3\u2010secretase. Additionally, BPN15606 rescued hyperactivation of Rab5, a protein responsible for regulating endosome function, and normalized neurotrophin signaling deficits. BPN15606 treatment also normalized the levels of synaptic proteins and tau phosphorylation, while reducing astrocytosis and microgliosis, and countering cognitive deficits.<\/jats:p><\/jats:sec><jats:sec><jats:title>Interpretation<\/jats:title><jats:p>Our findings point to the involvement of increased levels of A\u03b242 and\/or A\u03b240 in contributing to several molecular and cognitive traits associated with DS\u2010AD. They speak to increased dosage of the <jats:italic>APP<\/jats:italic> gene acting through heightened levels of A\u03b242 and\/or A\u03b240 as supporting pathogenesis. These findings further the interest in the potential use of \u03b3\u2010secretase modulators for treating and possibly preventing AD in individuals with DS. ANN NEUROL 2024;96:390\u2013404<\/jats:p><\/jats:sec>","DOI":"10.1002\/ana.26958","type":"journal-article","created":{"date-parts":[[2024,5,15]],"date-time":"2024-05-15T12:02:14Z","timestamp":1715774534000},"page":"390-404","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["<scp>\u03b3\u2010Secretase<\/scp> Modulator <scp>BPN15606<\/scp> Reduced A\u03b242 and A\u03b240 and Countered Alzheimer\u2010Related Pathologies in a Mouse Model of Down Syndrome"],"prefix":"10.1002","volume":"96","author":[{"given":"Xu\u2010Qiao","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann","family":"Becker","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Albay","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Phuong D.","family":"Nguyen","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitry","family":"Karachentsev","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda J.","family":"Roberts","sequence":"additional","affiliation":[{"name":"Animal Models Core Facility The Scripps Research Institute  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin D.","family":"Rynearson","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudolph E.","family":"Tanzi","sequence":"additional","affiliation":[{"name":"Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology Massachusetts General Hospital  Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6408-9548","authenticated-orcid":false,"given":"William C.","family":"Mobley","sequence":"additional","affiliation":[{"name":"Department of Neurosciences University of California San Diego  La Jolla CA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,15]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-019-0143-7"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(16)00063-6"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1706537"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2019.00659"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-018-0132-6"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-170624"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160836"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410430316"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2006.05.022"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3000258"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12463"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26659"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12835"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI82409"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.15252\/emmm.201606210"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20210077"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.117.240861"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.08.018"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20202560"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-190442"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-011-9356-0"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1074"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12185"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.3791\/52434"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.neubiorev.2004.06.006"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1023\/a:1021691918517"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0166-4328(88)90157-x"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beproc.2011.12.004"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/0165-0270(84)90007-4"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1037\/a0012807"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.neuro.24.1.897"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00335-016-9661-8"},{"key":"e_1_2_9_34_1","first-page":"263","article-title":"Segmental trisomy of murine chromosome 16: a new model system for studying down syndrome","volume":"360","author":"Davisson MT","year":"1990","journal-title":"Prog Clin Biol Res"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1038\/35052055"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.freeradbiomed.2017.10.341"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.201700359"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/mp.2015.97"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2019.01008"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(95)12052-6"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-021-00269-y"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30689-9"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2022.12910"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.100489"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2022.870517"},{"key":"e_1_2_9_46_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20170600"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00025"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.57078"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2018.00118"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1101\/2023.08.02.551596"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-9-48"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2022.30"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2212948"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2021.41"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.14283\/jpad.2023.30"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp2111320"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaneurol.2021.4161"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2020.05.019"}],"container-title":["Annals of Neurology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ana.26958","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,7,10]],"date-time":"2024-07-10T11:50:37Z","timestamp":1720612237000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ana.26958"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,15]]},"references-count":57,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,8]]}},"alternative-id":["10.1002\/ana.26958"],"URL":"https:\/\/doi.org\/10.1002\/ana.26958","archive":["Portico"],"relation":{},"ISSN":["0364-5134","1531-8249"],"issn-type":[{"value":"0364-5134","type":"print"},{"value":"1531-8249","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,15]]},"assertion":[{"value":"2023-11-28","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-15","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}