{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,30]],"date-time":"2025-12-30T23:25:25Z","timestamp":1767137125262,"version":"build-2238731810"},"reference-count":38,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2023,11,8]],"date-time":"2023-11-08T00:00:00Z","timestamp":1699401600000},"content-version":"vor","delay-in-days":38,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM068619"],"award-info":[{"award-number":["GM068619"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["alz-journals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["A&amp;amp;D Transl Res &amp;amp; Clin Interv"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Reducing brain levels of both soluble and insoluble forms of amyloid beta (A\u03b2) remains the primary goal of most therapies that target Alzheimer's disease (AD). However, no treatment has so far resulted in patient benefit, and clinical trials of the most promising drug candidates have generally failed due to significant adverse effects. This highlights the need for safer and more selective ways to target and modulate A\u03b2 biogenesis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Peptide technology has advanced to allow reliable synthesis, purification, and delivery of once\u2010challenging hydrophobic sequences. This is opening up new routes to target membrane processes associated with disease. Here we deploy a combination of atomic detail molecular dynamics (MD) simulations, living\u2010cell F\u00f6rster resonance energy transfer (FRET), and in vitro assays to elucidate the atomic\u2010detail dynamics, molecular mechanisms, and cellular activity and selectivity of a membrane\u2010active peptide that targets the A\u03b2 precursor protein (APP).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We demonstrate that A\u03b2 biogenesis can be downregulated selectively using an APP occlusion peptide (APPOP). APPOP inhibits A\u03b2 production in a dose\u2010dependent manner, with a mean inhibitory concentration (IC\n                      <jats:sub>50<\/jats:sub>\n                      ) of 450\u00a0nM toward exogenous APP and 50\u00a0nM toward endogenous APP in primary rat cortical neuronal cultures. APPOP does not impact the \u03b3\u2010secretase cleavage of Notch\u20101, or exhibit toxicity toward cultured primary rat neurons, suggesting that it selectively shields APP from proteolysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Drugs targeting AD need to be given early and for very long periods to prevent the onset of clinical symptoms. This necessitates being able to target A\u03b2 production precisely and without affecting the activity of key cellular enzymes such as \u03b3\u2010secretase for other substrates. Peptides offer a powerful way for targeting key pathways precisely, thereby reducing the risk of adverse effects. Here we show that protecting APP from proteolytic processing offers a promising route to safely and specifically lower A\u03b2 burden. In particular, we show that the amyloid pathway can be targeted directly and specificically. This reduces the risk of off\u2010target effects and paves the way for a safe prophylactic treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/trc2.12428","type":"journal-article","created":{"date-parts":[[2023,11,9]],"date-time":"2023-11-09T03:17:58Z","timestamp":1699499878000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Masking the transmembrane region of the amyloid \u03b2 precursor protein as a safe means to lower amyloid \u03b2 production"],"prefix":"10.1002","volume":"9","author":[{"given":"Ayesha","family":"Khan","sequence":"first","affiliation":[{"name":"EveBioTek Ltd. Trimble House  Warrington UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Richard","family":"Killick","sequence":"additional","affiliation":[{"name":"Living Systems Institute University of Exeter  Exeter UK"},{"name":"King's College London Maurice Wohl Clinical Neuroscience Institute  Camberwell London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniel","family":"Wirth","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering and Institute for NanoBioTechnology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dominique","family":"Hoogland","sequence":"additional","affiliation":[{"name":"Department of Chemistry King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kalina","family":"Hristova","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering and Institute for NanoBioTechnology Johns Hopkins University  Baltimore Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jakob P.","family":"Ulmschneider","sequence":"additional","affiliation":[{"name":"Institute of Natural Sciences Shanghai Jiao\u2010Tong University  Shanghai China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher R.","family":"King","sequence":"additional","affiliation":[{"name":"National Institutes of Health National Institute of Neurological Disorders and Stroke  Bethesda Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8103-0516","authenticated-orcid":false,"given":"Martin B.","family":"Ulmschneider","sequence":"additional","affiliation":[{"name":"Department of Chemistry King's College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2023,11,8]]},"reference":[{"key":"e_1_2_8_2_1","volume-title":"Global Health Estimates 2016: Deaths by Cause, Age, Sex, by Country and by Region, 2000\u20102016","author":"World Health Organisation","year":"2018"},{"key":"e_1_2_8_3_1","unstructured":"Office for National Statistics UK.Leading causes of death UK: 2001 to 2018.2020. 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