# Exploring the differential spreading of distinct pathological conformers of AD/LBD-related proteins by combining mathematical modeling and functional study

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2024 · $222,445

## Abstract

Project Summary
Alzheimer's Disease and Alzheimer's Disease Related Dementias (AD/ADRD) are characterized by the
deposition of pathological proteins, such as pathological tau in AD and coritcobasal degeneration (CBD),
among others, and pathological a-synuclein (a-syn) in Lewy body dementia (LBD). Transmission of pathological
proteins along the neuronal network is believed to be a key mechanism for disease progression. However, the
underlying molecular mechanisms that modulate this transmission process remain largely unknown. For one, it
is well documented that the conformational diversity of a-syn and tau contribute to disease heterogeneity, but it
is unclear how conformer type influences the progression of pathology. Further, the mediation of the disease
process by gene expression is incompletely understood, particularly in the context of network transmission.
Understanding these molecular mechanisms will provide critical insights into the selective vulnerability of
different brain regions to pathological protein transmission and identify new targets for drug development.
Here, we propose to identify candidate genes that are responsible for this selective regional vulnerability to
distinct pathological ɑ-Syn and tau conformations using mathematical modeling, thereby providing a heretofore
inaccessible, mechanistic understanding of the heterogeneity of AD/ADRD. We will combine our computational
approach with new in vivo mouse synucleinopathy and tauopathy datasets as well as a high-throughput in vitro
screening platform for the functional validation of genes. The focus on mouse proteinopathy is motivated by the
long track record of success in using these models as proxies for human disease and the high degree of
experimental control they afford. Our approach is novel both in terms of mathematical modeling and the
experimental systems explored.
In the first phase (R21) of our proposal, we will quantify the a-syn pathology induced by injecting 2 different
conformers: PFF and GCI. We will then apply a novel mathematical model, NexIS2, which explains the
accumulation and transmission of pathology over time in terms of both gene-independent and gene-mediated
processes, allowing us to identify in silico candidate genes that could be key mediators of disease progression.
These genes will be functionally validated with high-throughput in vitro screening of induced pathology in primary
neuron culture. The best genes will then be fed back into NexIS2 to create a comprehensive model of network
transmission for each conformer. In the second phase (R33), we will apply this established pipeline to identify
the key gene mediators of transmission for a third a-syn conformer (LB a-syn) and 2 distinct tau conformers (AD-
tau and CBD-tau). We will also examine the effect of amyloid on tauopathy progression in a joint mouse model
using NexIS2. Our approach could become a computational test bed for future hypothesis generation and
testing, and should have broader app...

## Key facts

- **NIH application ID:** 10934248
- **Project number:** 1R21AG087921-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Chao Peng
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $222,445
- **Award type:** 1
- **Project period:** 2024-09-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10934248

## Citation

> US National Institutes of Health, RePORTER application 10934248, Exploring the differential spreading of distinct pathological conformers of AD/LBD-related proteins by combining mathematical modeling and functional study (1R21AG087921-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10934248. Licensed CC0.

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