# Investigating the aggregation of amyloid β during metabolic stress using multiscale modeling

> **NIH NIH R21** · UNIVERSITY OF SOUTH FLORIDA · 2024 · $200,323

## Abstract

PROJECT SUMMARY
The oligomeric forms of two amyloid β (Aβ) peptides, Aβ40 and Aβ42, are considered as the primary toxic agents
in the etiology of Alzheimer’s disease (AD). However, the exact conditions leading to the onset and progression
of Aβ oligomerization in the brain remain largely unknown. Both in vivo and in vitro experiments show that Aβ
aggregation is promoted by increased Aβ concentrations, low pH, and elevated ionic strengths. These conditions
are transiently met in the extracellular space (ECS) in the brain during metabolic stress and spreading
depolarization (SD) associated with numerous pathologies, including ischemic stroke, aneurysmal subarachnoid
hemorrhage, traumatic brain injury, and migraine. All these conditions are risk factors for developing sporadic
AD. The low-pH conditions are also met in endo/lysosomes. Accordingly, we will test the hypothesis that
recurrent metabolic stress and SD events promote Aβ aggregation in the ECS and/or in endo/lysosomes. The
proposal further posits that short-term episodes of brain acidification and/or ion increases might result in different
populations of Aβ40 and/or Aβ42 aggregates than chronic, repetitive episodes. However, the wide range of
spatiotemporal scales involved and the dynamic nature of the complex interactions between different Aβ species
and physiochemical variables in the brain preclude testing these hypotheses through experiments alone.
 We propose to use novel approaches in multiscale modeling, high resolution microscopy, antibody staining,
and measurement of paralysis phenotype to determine the role of the drastic physiochemical changes due to
metabolic stress and SD in the onset and progression of Aβ40 and Aβ42 aggregation in the brain. We will achieve
this by using a range of innovative techniques: 1) high resolution imaging, optical spectroscopy, and
conformational-specific antibodies to determine how KCl, NaCl, pH, and Aβ concentration affect different
aggregate species of Aβ40 and Aβ42; 2) Markov chain models and Kinetic Monte Carlo algorithms to investigate
Aβ aggregation at a wide range of spatiotemporal scales from nanoseconds to months and nanometers to tens
of micrometers; 3) biophysical model for metabolic stress and SD, taking into account dynamic changes in ion
concentrations and pH in the ECS, neuron, and astrocyte; cell swelling and shrinkage of ECS; O2 homeostasis;
and neurovascular coupling; 4) detailed model for the function of endo/lysosomes under physiological conditions
and metabolic stress; 5) a comprehensive model to investigate the aggregation of Aβ40 and Aβ42 in the ECS
and endo/lysosomes in the neuron and astrocyte simultaneously in brain region-specific manner; and 6) paralysis,
phenotype, antibody staining, and microscopy to test model predictions in the C. elegans strain JKM7 expressing
the human Aβ42 peptide. In addition to understanding the conditions leading to the aggregation of Aβ40 and
Aβ42 at spatiotemporal scales that are not possible t...

## Key facts

- **NIH application ID:** 10933870
- **Project number:** 1R21AG087910-01
- **Recipient organization:** UNIVERSITY OF SOUTH FLORIDA
- **Principal Investigator:** MARTIN MUSCHOL
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $200,323
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933870

## Citation

> US National Institutes of Health, RePORTER application 10933870, Investigating the aggregation of amyloid β during metabolic stress using multiscale modeling (1R21AG087910-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10933870. Licensed CC0.

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