{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T10:50:36Z","timestamp":1791370236986,"version":"4.3.1"},"reference-count":46,"publisher":"Oxford University Press (OUP)","license":[{"start":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T00:00:00Z","timestamp":1791331200000},"content-version":"am","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"name":"Canadian Institute for Health and Research","award":["MOP-97776"],"award-info":[{"award-number":["MOP-97776"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["HD38466"],"award-info":[{"award-number":["HD38466"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UCI\u2019s Alzheimer\u2019s Disease Research Center","award":["AG16573"],"award-info":[{"award-number":["AG16573"]}]},{"name":"National Institutes on Aging","award":["AG012122"],"award-info":[{"award-number":["AG012122"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes on Aging","award":["AG08051"],"award-info":[{"award-number":["AG08051"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes on Aging","award":["NS073502"],"award-info":[{"award-number":["NS073502"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"crossref"}]},{"DOI":"10.13039\/100008582","name":"McGill University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008582","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Charles E. Frosst\/Merck Chair in Pharmacology"},{"DOI":"10.13039\/501100000143","name":"Alzheimer Society of Canada","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100000143","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Charles E. Frosst-Merck Post-Doctoral Fellowship"},{"DOI":"10.13039\/501100003141","name":"National Council for Science and Technology","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003141","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Basal forebrain cholinergic neurons play a key role in cognition. This neuronal system is highly dependent on nerve growth factor (NGF) for its synaptic integrity and the phenotypic maintenance of its cell bodies. Basal forebrain cholinergic neurons progressively degenerate in Alzheimer\u2019s disease and Down\u2019s syndrome, and their atrophy contributes to the manifestation of dementia. Paradoxically, in Alzheimer\u2019s disease brains, the synthesis of NGF is not affected and there is abundance of the NGF precursor (proNGF). We have shown that this phenomenon is due to a deficit in NGF\u2019s extracellular metabolism which compromises proNGF maturation and exacerbates its subsequent degradation. We hypothesized that a similar imbalance should be present in Down\u2019s syndrome. Using a combination of quantitative reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, western blotting and zymography, we have investigated signs of NGF metabolic dysfunction in post-mortem brains from the temporal (n = 14), frontal (n = 34) and parietal (n = 20) cortex obtained from Down\u2019s syndrome subjects and age-matched controls (age range 31\u201368 years). We further examined primary cultures of human fetal Down\u2019s syndrome cortex (17\u201321 gestational age weeks). We report a significant increase in proNGF levels in human Down\u2019s syndrome brains, with a concomitant reduction in the levels of plasminogen and tissue plasminogen activator mRNA as well as an increment in neuroserpin expression; enzymes that partake in proNGF maturation. Down\u2019s syndrome brains also exhibited elevated zymogenic activity of MMP9, the major NGF-degrading protease. Our results indicate a failure in proNGF maturation in Down\u2019s syndrome brains and a likely enhanced proteolytic degradation of NGF, changes which can compromise the trophic support of basal forebrain cholinergic neurons. The alterations in proNGF and MMP9 were also present in cultures of Down\u2019s syndrome fetal cortex; suggesting that this trophic compromise may be amenable to rescue, before frank dementia onset. Our study thus provides a novel paradigm for cholinergic neuroprotection in Alzheimer\u2019s disease and Down\u2019s syndrome.<\/jats:p>","DOI":"10.1093\/brain\/awag238","type":"journal-article","created":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T10:01:48Z","timestamp":1791367308000},"source":"Crossref","is-referenced-by-count":0,"title":["Nerve growth factor metabolic dysfunction in Down\u2019s syndrome brains"],"prefix":"10.1093","author":[{"given":"M Florencia","family":"Iulita","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University , Montreal, H3G1Y6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Do Carmo","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University , Montreal, H3G1Y6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alison K","family":"Ower","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University , Montreal, H3G1Y6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley M","family":"Fortress","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and the Center on Aging, Medical University of South Carolina , Charleston, SC 29425 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisi","family":"Flores Aguilar","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, McGill University , Montreal, H3G1Y6 ,","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Hanna","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, University of California , Irvine, CA 92697 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Wisniewski","sequence":"additional","affiliation":[{"name":"Department of Neurology, Pathology and Psychiatry, New York University School of Medicine , New York, NY 10016 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Charlotte","family":"Granholm","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and the Center on Aging, Medical University of South Carolina , Charleston, SC 29425 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mona","family":"Buhusi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences and the Center on Aging, Medical University of South Carolina , Charleston, SC 29425 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jorge","family":"Busciglio","sequence":"additional","affiliation":[{"name":"Department of Neurobiology and Behavior, University of California , Irvine, CA 92697 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A Claudio","family":"Cuello","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, McGill University , Montreal, H3G1Y6 ,","place":["Canada"]},{"name":"Department of Anatomy and Cell Biology, McGill University , Montreal, H3G1Y6 ,","place":["Canada"]},{"name":"Department of Neurology and Neurosurgery, McGill University , Montreal , H3G1Y6","place":["Canada"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,10,7]]},"reference":[{"key":"2026100706014210800_awag238-B1","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/B978-0-444-54299-1.00006-6","article-title":"Neurological phenotypes for Down syndrome across the life span","volume":"197","author":"Lott","year":"2012","journal-title":"Prog Brain 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