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Shrinking of Extracellular Space During Metabolic Stress Accelerates Amyloid-β Aggregation
Laura F De Oliveira1, Kanchana Karunarathne1, Dalton Zona1
1Department of Physics, University of South Florida, Tampa, FL 33620, USA.
Biomolecules
|July 28, 2026
Summary
Metabolic stress, like that from brain injury, accelerates Alzheimer's disease (AD) pathology by altering amyloid-beta (Aβ42) aggregation through changes in the brain's extracellular space (ECS). This study quantifies how these events impact Aβ42 aggregation kinetics.
Area of Science:
- Neuroscience
- Biochemistry
- Computational Biology
Background:
- Metabolic stress conditions like traumatic brain injury (TBI), hypoxia, stroke, and migraine are risk factors for Alzheimer's disease (AD).
- The precise mechanisms linking these pathological states to AD progression are not fully understood.
- Spreading depolarization (SD) is a key event in these conditions, involving dynamic changes in the brain's extracellular space (ECS).
Purpose of the Study:
- To investigate how metabolic stress, specifically through spreading depolarization (SD), influences amyloid-beta (Aβ42) aggregation kinetics.
- To elucidate the role of dynamic changes in the extracellular space (ECS) during SD in modulating Aβ42 aggregation.
- To develop a computational framework for understanding the interplay between metabolic stress, ECS dynamics, and Aβ42 aggregation.
Main Methods:
- Utilized ThT fluorescence assays to analyze Aβ42 aggregate species formation at varying concentrations.
- Developed a multiscale computational model integrating neuronal volume regulation, ion homeostasis, and Aβ42 aggregation kinetics.
- Simulated the effects of SD events on ECS volume and Aβ42 aggregation under different conditions.
Main Results:
- Neuronal swelling during SD accelerates Aβ42 aggregation, with effects dependent on the timing and initial monomer concentration.
- Early SD events promote off-pathway oligomer formation at low Aβ42 concentrations and rapid fibril formation at high concentrations.
- Recurrent metabolic stress amplifies oligomer accumulation in the absence of fibrils, while existing fibrils suppress oligomer formation.
- Increased metabolic stress intensity prolongs ECS shrinkage and enhances oligomer formation.
Conclusions:
- Established a mechanistic link between SD-induced microenvironmental changes and Aβ aggregation dynamics.
- Provided a quantitative framework for understanding how acute brain injury and metabolic stress contribute to early AD pathogenesis.
- Highlighted the critical role of ECS dynamics and metabolic stress timing in modulating Aβ aggregation pathways.
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