{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,8]],"date-time":"2026-01-08T07:44:18Z","timestamp":1767858258589,"version":"3.49.0"},"reference-count":23,"publisher":"MDPI AG","issue":"8","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\/4.0\/"}],"funder":[{"name":"National Institutes of Health","award":["R01AG067331"],"award-info":[{"award-number":["R01AG067331"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Niemann\u2013Pick disease type C (NPC) is a rare and fatal neurological disorder caused by mutations in Npc1 or Npc2, with Npc1 accounting for 95% of cases. These mutations result in the functional loss of their respective proteins, causing cellular abnormalities characterized by disrupted lipid dysregulation, calcium dysfunction, elevated damage associated molecular patterns (DAMPs), and a pro-inflammatory environment. This cellular pathology ultimately triggers neurodegeneration, with the cerebellum being the earliest and most affected region. We have recently shown atypical activation of interferon signaling in the presymptomatic Npc1\u2212\/\u2212 mouse cerebellum and, to a lesser extent, in the cerebral cortex. In addition, we reported that the Amyloid Precursor Protein (APP) is an NPC disease modifier. Loss of APP function leads to widespread neurodegeneration in the NPC brain, including exacerbated interferon signaling in the cerebellum. To better understand the role of APP as a disease modifier throughout the NPC brain, here we carried out a transcriptomic analysis of the cerebral cortex and cerebellum from 3-week-old Npc1\u2212\/\u2212 mice as well as age-matched controls in the presence and absence of APP. We report differential effects of APP loss of function in the cerebral cortex and cerebellum, including cholesterol and tau dysregulation, in both brain regions. Our findings demonstrate a novel link between APP loss and early pathogenic mechanisms in NPC.<\/jats:p>","DOI":"10.3390\/genes15081066","type":"journal-article","created":{"date-parts":[[2024,8,13]],"date-time":"2024-08-13T06:02:37Z","timestamp":1723528957000},"page":"1066","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A Potential Role for the Amyloid Precursor Protein in the Regulation of Interferon Signaling, Cholesterol Homeostasis, and Tau Phosphorylation in Niemann\u2013Pick Disease Type C"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3974-1570","authenticated-orcid":false,"given":"Kayla L.","family":"Sanchez","sequence":"first","affiliation":[{"name":"Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Samuel D.","family":"Shin","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naren P.","family":"Rajagopal","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacob B.","family":"White","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4142-7054","authenticated-orcid":false,"given":"Antonio","family":"Currais","sequence":"additional","affiliation":[{"name":"The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1235-1671","authenticated-orcid":false,"given":"David","family":"Soriano-Castell","sequence":"additional","affiliation":[{"name":"The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0694-0610","authenticated-orcid":false,"given":"Pamela","family":"Maher","sequence":"additional","affiliation":[{"name":"The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6369-4586","authenticated-orcid":false,"given":"Salvador","family":"Soriano","sequence":"additional","affiliation":[{"name":"Department of Pathology and Human Anatomy, School of Medicine, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.ymgme.2021.06.011","article-title":"Estimating the prevalence of Niemann-Pick disease type C (NPC) in the United States","volume":"134","author":"Burton","year":"2021","journal-title":"Mol. 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