{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T05:20:36Z","timestamp":1791523236595,"version":"4.3.4"},"reference-count":44,"publisher":"MDPI AG","issue":"20","license":[{"start":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T00:00:00Z","timestamp":1760659200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the NSF, Office of Advanced Cyberinfrastructure","award":["OAC # 2018551"],"award-info":[{"award-number":["OAC # 2018551"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) has been studied extensively and is characterized by plaques deposited throughout the brain. Plaques are made of beta-amyloid (A\u03b2) peptides which have undergone fibrillogenesis to form insoluble A\u03b2 fibrils (fA\u03b2) that are neurotoxic. Receptor for Advanced Glycation End end products (RAGE), toll-like receptors (TLRs) 2 and 4, and co-receptor CD14 recognize negatively charged binding regions on fA\u03b2 to activate microglia and release proinflammatory cytokines. In this study, we used two experimentally resolved fA\u03b2 structures (type I and II) isolated from AD brain tissue to elucidate binding patterns of fA\u03b2 with RAGE, TLR2, TLR4, and CD14 and investigated whether binding was affected by fibril structure or system pH. Receptors TLR2 and RAGE formed tight complexes with both type I and II fibrils, while TLR4 showed selectivity for type I. CD14 binding was less tight and selective for type II. Binding was pH dependent for CD14, TLR4, and RAGE but not TLR2. We explored the effects of familial mutations on fibril structure to determine whether mutants of type I or II structures are feasible. Finally, we investigated whether mutations affected binding interactions of fA\u03b2 with proteins. The Arctic (Glu22Gly), Dutch (Glu22Gln), and Iowa (Asp23Asn) mutations showed similar effects on binding affinity. Italian (Glu22Lys) mutations abrogated binding, whereas type I and II fibrils with Flemish (Ala21Gly) mutations were not shown to be feasible. Results highlight the adaptability of immune receptors in recognizing damaging molecules, with fibril structure and pH being the main recognition determinants predicated on disease progression. In silico mutations showed that aggregates similar to type I and II structures were plausible for some familial mutations.<\/jats:p>","DOI":"10.3390\/molecules30204116","type":"journal-article","created":{"date-parts":[[2025,10,17]],"date-time":"2025-10-17T10:28:36Z","timestamp":1760696916000},"page":"4116","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Factors Driving Amyloid Beta Fibril Recognition by Cell Surface Receptors: A Computational Study"],"prefix":"10.3390","volume":"30","author":[{"given":"Olivia","family":"Slater","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Sciences, Southern Illinois University, Edwardsville, IL 62026, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Kontoyianni","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Sciences, Southern Illinois University, Edwardsville, IL 62026, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e105","DOI":"10.1016\/S2468-2667(21)00249-8","article-title":"Estimation of the global prevalence of dementia in 2019 and forecasted prevalence in 2050: An analysis for the Global Burden of Disease Study 2019","volume":"7","author":"Nichols","year":"2022","journal-title":"Lancet Public Health"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.neurobiolaging.2020.12.007","article-title":"Decreased pH in the aging brain and Alzheimer\u2019s disease","volume":"101","author":"Decker","year":"2021","journal-title":"Neurobiol. 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