# A Mouse Model for Braak I/II Alzheimer's Pathology

> **NIH NIH R21** · UNIVERSITY OF WISCONSIN-MADISON · 2024 · $226,590

## Abstract

ABSTRACT:
The goal of this study is to characterize a novel mouse mutant with a phenotype resembling Braak
stage I/II Alzheimer’s disease (AD) pathology in humans and to develop this line into a novel animal
model for AD research. AD is a major public health crisis predicted to affect 13.8 million Americans and
cost $750 billion per year by 2050. However, the pathological mechanisms underlying AD have
remained controversial, especially regarding how amyloidosis, tauopathy, and neuroinflammation, the
three hallmarks of AD, may interact with each other at the molecular and cellular level to promote AD
pathology development. This uncertainty has impeded the development of effective intervention. In
pilot studies, we have generated a microglia-specific mouse mutant with strong tauopathy and atrophy
specifically in the entorhinal cortex. This is the first time such a unique tauopathy phenotype has been
observed in the mouse brain. In humans, tauopathy in the entorhinal cortex predicts not only that rate of
future tau pathology spread and deterioration in the brain but also the rate of cognitive decline in
affected patients. Thus, the mouse mutant we have provides a unique opportunity for uncovering
mechanisms of tauopathy development in AD. To characterize this mutant, we will:
 1) determine spatial and temporal pathologic progression across cell types in the mutant brain
 2) identify key cellular/molecular drivers of the tauopathy phenotype
Through these experiments, we will determine primary and secondary changes in the various brain cell
types in the mutant brain and pave way for elucidation of mechanisms of AD tauopathy development in
this unique mouse model. We will also gain insight into the mechanisms by which inflammatory
cytokines may drive entorhinal tauopathy in this mutant and pave way for determining the functional
significance. Together, through this study, we will provide not only a novel AD animal model with strong
entorhinal tauopathy and neurodegeneration yet no complications of gene overexpression.
Furthermore, since the predominant group of risk genes for late-onset AD, which comprises >95% of
AD cases, are related to microglial function, we will also provide a model to elucidate pathogenic
mechanisms of tauopathy that are specific and relevant to the vast majorities of AD cases.

## Key facts

- **NIH application ID:** 10984691
- **Project number:** 1R21AG085588-01A1
- **Recipient organization:** UNIVERSITY OF WISCONSIN-MADISON
- **Principal Investigator:** Zhen Huang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $226,590
- **Award type:** 1
- **Project period:** 2024-09-15 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10984691

## Citation

> US National Institutes of Health, RePORTER application 10984691, A Mouse Model for Braak I/II Alzheimer's Pathology (1R21AG085588-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10984691. Licensed CC0.

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