{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T06:04:26Z","timestamp":1790057066952,"version":"4.0.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T00:00:00Z","timestamp":1790035200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Aging Neurosci."],"abstract":"<jats:p>\n                    Alzheimer\u2019s disease (AD) pathology is amplified by a self-reinforcing metal\u2013A\u03b2\u2013ROS axis, in which redox-active Cu and Fe bound to A\u03b2 N-terminal histidines catalyze Fenton-like ROS generation and accelerate aggregation. Existing single-target interventions \u2013 anti-amyloid antibodies, antioxidants, metal-protein attenuating compounds, aggregation inhibitors, and photooxygenation catalysts \u2013 each address only one node of this loop. We used a computational-first framework to evaluate a dual-function strategy targeting two connected points of the axis: upstream redox-active metal sequestration by maltol, and downstream photodynamic modification of A\u03b2 aggregates via endogenous protoporphyrin IX (PpIX), generated from 5-aminolevulinic acid (5-ALA) under 400 nm illumination.\n                    <jats:italic>Drosophila<\/jats:italic>\n                    experiments served as functional validation, testing whether this combined intervention improved A\u03b242-associated behavioral and survival outcomes and was tolerated in wild-type (WT) flies. DFT calculations (B3LYP-D3BJ\/def2-SVP\/\/def2-TZVP, CPCM\/SMD water) showed deprotonated maltol localizes oxygen-donor electron density comparable to deprotonated deferiprone, and forms a converged, solvent-stabilized Fe(III)\u2013maltol complex. Cu(II) and Zn(II) coordination was weak and geometrically incomplete, indicating an Fe-preferential rather than broadly nonspecific chelation profile; the study does not demonstrate protection against Cu(II)-mediated ROS. Time-dependent DFT predicted PpIX excitations spanning the visible\/near-UV range consistent with photosensitizer behavior, and docking against A\u03b242 fibril 5OQV showed PpIX engaged the central hydrophobic\/turn surface more strongly than chlorin e6 or maltol. In a pan-neuronal A\u03b242\n                    <jats:italic>Drosophila<\/jats:italic>\n                    model, dual treatment improved climbing performance (\n                    <jats:italic>p<\/jats:italic>\n                    = 2.39 \u00d7 10\n                    <jats:sup>\u22123<\/jats:sup>\n                    vs. untreated A\u03b242) and extended lifespan (log-rank\n                    <jats:italic>p<\/jats:italic>\n                    = 6.04 \u00d7 10\n                    <jats:sup>\u221213<\/jats:sup>\n                    ; median survival \u223c40 d); WT + Treatment flies appeared tolerant, though no formal statistical contrast was pre-specified. Treatment-group ThT amyloid burden was not measured, so no amyloid-reduction claim is made. Because chelation-only and 5-ALA\/light-only arms were not included, we cannot attribute improvement to either intervention alone and cannot make a formal claim of additive or interactive effects between the two intervention components. The combined intervention was associated with improved behavioral and survival outcomes in the A\u03b242\n                    <jats:italic>Drosophila<\/jats:italic>\n                    model. Because the present study lacks single-intervention controls and treatment-group pathological measurements, these findings do not establish the mechanism responsible for the observed functional improvement. The study illustrates how ground-state, excited-state, and docking calculations can jointly inform a computationally motivated intervention tested in a tractable organismal model.\n                  <\/jats:p>","DOI":"10.3389\/fnagi.2026.1912315","type":"journal-article","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T05:38:57Z","timestamp":1790055537000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["A computational-first proof-of-concept for dual-function metal chelation and aggregate neutralization in an A\u03b242 Drosophila model"],"prefix":"10.3389","volume":"18","author":[{"given":"Edric","family":"Tsai","sequence":"first","affiliation":[{"name":"Great Neck South High School","place":["Great Neck, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zimu","family":"Wang","sequence":"additional","affiliation":[{"name":"Great Neck South High School","place":["Great Neck, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Truglio","sequence":"additional","affiliation":[{"name":"Great Neck South High School","place":["Great Neck, NY, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"250","DOI":"10.3322\/caac.20114","article-title":"Photodynamic therapy of cancer: An update.","volume":"61","author":"Agostinis","year":"2011","journal-title":"CA. 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