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Despite enormous efforts that have been spent in the last decades to find effective therapies, late pharmacological interventions along the course of the disease, inaccurate clinical methodologies in the enrollment of patients, and inadequate biomarkers for evaluating drug efficacy have not allowed the development of an effective therapeutic strategy. The approaches followed so far for developing drugs or antibodies focused solely on targeting A\u03b2 or tau protein. This paper explores the potential therapeutic capacity of an all-D-isomer synthetic peptide limited to the first six amino acids of the N-terminal sequence of the A2V-mutated A\u03b2, A\u03b21-6<jats:sub>A2V<\/jats:sub>(D), that was developed following the observation of a clinical case that provided the background for its development. We first performed an in-depth biochemical characterization documenting the capacity of A\u03b21-6<jats:sub>A2V<\/jats:sub>(D) to interfere with the aggregation and stability of tau protein. To tackle A\u03b21-6<jats:sub>A2V<\/jats:sub>(D) in vivo effects against a neurological decline in genetically predisposed or acquired high AD risk mice, we tested its effects in triple transgenic animals harboring human PS1(M146 V), APP(SW), and MAPT(P301L) transgenes and aged wild-type mice exposed to experimental traumatic brain injury (TBI), a recognized risk factor for AD. We found that A\u03b21-6<jats:sub>A2V<\/jats:sub>(D) treatment in TBI mice improved neurological outcomes and reduced blood markers of axonal damage. Exploiting the <jats:italic>C. elegans<\/jats:italic> model as a biosensor of amyloidogenic proteins\u2019 toxicity, we observed a rescue of locomotor defects in nematodes exposed to the brain homogenates from TBI mice treated with A\u03b21-6<jats:sub>A2V<\/jats:sub>(D) compared to TBI controls. By this integrated approach, we demonstrate that A\u03b21-6<jats:sub>A2V<\/jats:sub>(D) not only impedes tau aggregation but also favors its degradation by tissue proteases, confirming that this peptide interferes with both A\u03b2 and tau aggregation propensity and proteotoxicity.<\/jats:p>","DOI":"10.1038\/s41380-023-02101-3","type":"journal-article","created":{"date-parts":[[2023,5,17]],"date-time":"2023-05-17T10:02:37Z","timestamp":1684317757000},"page":"2433-2444","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A\u03b21-6A2V(D) peptide, effective on A\u03b2 aggregation, inhibits tau misfolding and protects the brain after traumatic brain injury"],"prefix":"10.1038","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2258-0531","authenticated-orcid":false,"given":"Luisa","family":"Diomede","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa R.","family":"Zanier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2682-5583","authenticated-orcid":false,"given":"Federico","family":"Moro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gloria","family":"Vegliante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Colombo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Russo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfredo","family":"Cagnotto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmina","family":"Natale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica Marta","family":"Xodo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ada","family":"De Luigi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4409-8516","authenticated-orcid":false,"given":"Michele","family":"Mosconi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marten","family":"Beeg","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcella","family":"Catania","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giacomina","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1039-7315","authenticated-orcid":false,"given":"Fabrizio","family":"Tagliavini","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3537-6713","authenticated-orcid":false,"given":"Giuseppe","family":"Di Fede","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9098-9873","authenticated-orcid":false,"given":"Mario","family":"Salmona","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,5,17]]},"reference":[{"key":"2101_CR1","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1001\/jamaneurol.2013.5847","volume":"71","author":"GS Bloom","year":"2014","unstructured":"Bloom GS. 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