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A prime example is the amyloidogenic processing of amyloid precursor protein (APP) in intracellular vesicles, which plays a key role in age-related cognitive impairment. Most approaches to correct this altered processing aim to limit enzymatic activities that lead to toxic products, such as protein cleavage by \u03b2-secretase and the resulting amyloid \u03b2 production. A viable alternative is to direct APP to cellular compartments where non-amyloidogenic mechanisms are favored. To this end, we exploited the molecular properties of the herpes simplex virus 1 (HSV-1) transport protein US9 to guide APP interaction with preferred endogenous targets. Specifically, we generated a US9 chimeric construct that facilitates APP processing through the non-amyloidogenic pathway and tested it in primary cortical neurons. In addition to reducing amyloid \u03b2 production, our approach controls other APP-dependent biochemical steps that lead to neuronal deficits, including phosphorylation of APP and tau proteins. Notably, it also promotes the release of neuroprotective soluble \u03b1APP. In contrast to other neuroprotective strategies, these US9-driven effects rely on the activity of endogenous neuronal proteins, which lends itself well to the study of fundamental mechanisms of APP processing\/trafficking. Overall, this work introduces a new method to limit APP misprocessing and its cellular consequences without directly targeting secretase activity, offering a novel tool to reduce cognitive decline in pathologies such as Alzheimer\u2019s disease and HIV-associated neurocognitive disorders.<\/jats:p>","DOI":"10.1007\/s12035-022-03153-2","type":"journal-article","created":{"date-parts":[[2022,12,28]],"date-time":"2022-12-28T05:02:46Z","timestamp":1672203766000},"page":"1811-1825","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["The US9-Derived Protein gPTB9TM Modulates APP Processing Without Targeting Secretase Activities"],"prefix":"10.1007","volume":"60","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3078-9009","authenticated-orcid":false,"given":"Renato","family":"Brandimarti","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elena","family":"Irollo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8333-4804","authenticated-orcid":false,"given":"Olimpia","family":"Meucci","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2022,12,28]]},"reference":[{"key":"3153_CR1","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1126\/science.1566067","volume":"256","author":"JA Hardy","year":"1992","unstructured":"Hardy JA, Higgins GA (1992) Alzheimer\u2019s disease: the amyloid cascade hypothesis. 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