{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:23:36Z","timestamp":1785425016746,"version":"3.56.0"},"reference-count":81,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T00:00:00Z","timestamp":1784332800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AG087910"],"award-info":[{"award-number":["R21AG087910"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R21AG087910"],"award-info":[{"award-number":["R21AG087910"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Pathological states associated with metabolic stress, such as traumatic brain injury (TBI), hypoxia, ischemic stroke, and migraine, are considered elevated risk factors for developing Alzheimer\u2019s disease (AD). However, the mechanism underlying the effect of these conditions on the progression of AD remains largely unknown. Here, we determine how metabolic stress associated with spreading depolarization (SD)\u2014a hallmark of stroke, hypoxia, TBI, and migraine\u2014modulates amyloid \u03b2 (A\u03b242) aggregation kinetics through dynamic changes in extracellular space (ECS). To achieve this, we used ThT fluorescence to determine how the formation of different A\u03b242 aggregate species depends on A\u03b242 concentrations. Based on this input, we build a multiscale computational framework that integrates volume regulation, including its dependence on neuronal ion homeostasis, and A\u03b242 aggregation kinetics. Our model predicts that neuronal swelling during SD accelerates aggregation, where the impact of metabolic stress is highly dependent on the timing relative to aggregation progression and the initial monomer concentration. At low monomer concentrations, early SD events promote off-pathway oligomer formation, while at higher concentrations they rapidly drive fibril formation to saturation. In the absence of mature fibrils, recurrent metabolic stress events further amplify oligomer accumulation, whereas pre-existing fibril nuclei suppress oligomer formation at the expense of fibril nucleation and growth. Increasing the intensity of metabolic stress prolongs ECS shrinkage and enhances oligomer formation. These findings reveal a mechanistic link between SD-induced microenvironmental changes and A\u03b2 aggregation dynamics, providing a quantitative framework for understanding how acute brain injury and metabolic stress may contribute to early AD pathogenesis.<\/jats:p>","DOI":"10.3390\/biom16071053","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:47:32Z","timestamp":1784508452000},"page":"1053","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Shrinking of Extracellular Space During Metabolic Stress Accelerates Amyloid-\u03b2 Aggregation"],"prefix":"10.3390","volume":"16","author":[{"given":"Laura F","family":"De Oliveira","sequence":"first","affiliation":[{"name":"Department of Physics, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanchana","family":"Karunarathne","sequence":"additional","affiliation":[{"name":"Department of Physics, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dalton","family":"Zona","sequence":"additional","affiliation":[{"name":"Department of Physics, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Muschol","sequence":"additional","affiliation":[{"name":"Department of Physics, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3716-8742","authenticated-orcid":false,"given":"Ghanim","family":"Ullah","sequence":"additional","affiliation":[{"name":"Department of Physics, University of South Florida, Tampa, FL 33620, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1126\/science.1072994","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease: Progress and problems on the road to therapeutics","volume":"297","author":"Hardy","year":"2002","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1126\/science.1566067","article-title":"Alzheimer\u2019s disease: The amyloid cascade hypothesis","volume":"256","author":"Hardy","year":"1992","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1152\/jn.00090.2012","article-title":"A neuronal population in hypothalamus that dramatically resists acute ischemic injury compared to neocortex","volume":"108","author":"Brisson","year":"2012","journal-title":"J. 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