# Determining the role of tissue stiffness in the development of Alzheimer's disease pathology

> **NIH NIH R21** · UNIVERSITY OF COLORADO DENVER · 2024 · $188,825

## Abstract

PROJECT SUMMARY
 Alzheimer's disease is the most common form of dementia, and exerts an untold burden on
patients, families and caregivers, and the U.S. healthcare system. Alzheimer's disease is a progressive
neurodegenerative disorder caused by the accumulation of amyloid plaques and neurofibrillary tangles
(NFTs) in the brain, the two neuropathological hallmarks of Alzheimer's disease. Much effort has been
devoted to understanding the molecular mechanisms of amyloid and NFT accumulation, and the majority
of therapeutic approaches thus far have targeted these pathways. However, the field has yet to produce
an effective therapeutic for Alzheimer's disease that can convincingly slow, halt or reverse this
devastating illness. Recently, the biomechanical properties of brain tissues have emerged as a potentially
useful biomarker, as the brains of Alzheimer's disease patients have been consistently shown to have
decreased mechanical stiffness relative to those of healthy subjects. These biomechanical changes are
likely due to a combination of the effects of neurodegeneration and changes to the composition and
structure of brain extracellular matrix (BECM). Importantly, neurodegeneration correlates well with clinical
symptoms of Alzheimer's disease, whereas changes in the BECM occur years to decades prior to
cognitive decline, suggesting that they are intricately connected with disease pathogenesis. Herein, we
propose to systematically evaluate the contribution of BECM biomechanical properties to the development
of Alzheimer's disease neuropathology. Unfortunately, in vivo models offer very limited capacity to
regulate the mechanical stiffness of brain tissue. Therefore, we have developed novel three-dimensional
(3D) decellularized BECM-based models with tunable mechanical properties, and have demonstrated that
we can vary the model stiffness within the range of normal and Alzheimer's disease human brain tissue.
We have also developed 3D cerebral organoid (CO) models using human induced pluripotent stem cells
(hiPSCs) derived from Alzheimer's disease patients or from healthy controls (HC). We found that, relative
to HC COs, Alzheimer's disease COs have decreased mechanical stiffness and develop progressive
amyloid plaques and NFTs and neurodegeneration. Herein, we propose to embed COs within 3D BECM
models, enabling high-throughput experimentation of the relationship between tissue biomechanics and
Alzheimer's disease pathophysiology. We will test the hypothesis that the Alzheimer's disease
neuropathology within the CO is intricately linked with BECM mechanical properties, and that increasing
the BECM mechanical stiffness will reduced Alzheimer's disease phenotypes. These experiments will
establish 3D BECM-CO as a new tool for investigation at the intersection of tissue biomechanics and
disease pathobiology, and aims to identify a new mechanistic pathway contributing to Alzheimer's disease
that has the potential to be modified therapeutically to alter ...

## Key facts

- **NIH application ID:** 10747977
- **Project number:** 5R21AG080257-02
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Noah Ray Johnson
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $188,825
- **Award type:** 5
- **Project period:** 2022-12-15 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10747977

## Citation

> US National Institutes of Health, RePORTER application 10747977, Determining the role of tissue stiffness in the development of Alzheimer's disease pathology (5R21AG080257-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10747977. Licensed CC0.

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