# Network and cellular vulnerability to pathological protein progression

> **NIH NIH R01** · VAN ANDEL RESEARCH INSTITUTE · 2024 · $441,969

## Abstract

PROJECT SUMMARY/ABSTRACT
Over 6.5 million people in the United States currently live with progressive neurodegenerative Alzheimer’s
disease (AD) and related dementias including dementia with Lewy bodies (DLB), yet no treatments to stop their
progression are available. The presence of aggregated proteins in the brain (tau, amyloid β (Aβ), and α-
synuclein) is thought to underlie disease, and clinical overlap in presentation of these diseases associates with
the presence of more than one type of pathology. The factors influencing cellular and network vulnerability to
each individual pathology or co-occurring pathologies are not well-understood. A proper understanding of
vulnerability in the context of co-pathologies is necessary for the development and evaluation of novel disease-
modifying treatments.
This project will test the hypothesis that progression of intracellular α-synuclein and tau pathologies are bound
by neuroanatomical connectivity but influenced by network and cell-level vulnerability. Network and cell-level
vulnerability may also be influenced by additional factors such as the presence of co-pathologies, including
extracellular amyloid β (Aβ) plaques. To test this hypothesis, the following aims will be pursued: (i) progression
of α-synuclein and tau pathologies will be mapped in wildtype mice bearing single or multiple pathologies at high
resolution using registration to a common neuroanatomical atlas, and network parameters of progression will be
assessed with computational modeling (Specific Aim 1); quantitative pathology and network analysis will be
utilized to assess the impact of Aβ plaques on the development, spread, and network vulnerability to α-synuclein
and tau co-pathology in knock-in mice that express human tau and develop Aβ plaques and in a time-dependent
manner (Specific Aim 2); spatial transcriptomics of human AD brain, DLB brain, and mouse co-pathology brain
will be used to determine unique molecular signatures of neurons vulnerable to α-synuclein or tau pathologies.
Vulnerability signatures will be validated with combined in situ hybridization-immunofluorescence and integrated
with network vulnerability and regional gene expression to develop and evaluate a model of human co-pathology
progression as a resource for understanding disease progression and evaluating therapeutic efficacy (Specific
Aim 3).
The proposed research is expected to improve our understanding of the spatiotemporal progression of co-
pathologies and to develop improved tools to evaluate efficacy of novel therapeutic strategies that could slow
the progression of neurodegenerative diseases.

## Key facts

- **NIH application ID:** 10832610
- **Project number:** 5R01AG077573-03
- **Recipient organization:** VAN ANDEL RESEARCH INSTITUTE
- **Principal Investigator:** Michael Henderson
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $441,969
- **Award type:** 5
- **Project period:** 2022-05-01 → 2027-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10832610

## Citation

> US National Institutes of Health, RePORTER application 10832610, Network and cellular vulnerability to pathological protein progression (5R01AG077573-03). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10832610. Licensed CC0.

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