# Develop and Validate a Mouse Model for Alzheimer Disease in Down Syndrome

> **NIH NIH R61** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2024 · $1,698,323

## Abstract

Alzheimer disease (AD) exacts enormous personal and financial burdens in the aging. People with Down syndrome (DS) (i.e., trisomy 21, HSA21) are at markedly increased risk of AD, a disorder called DS-AD. The clinical and pathological hallmarks of AD are replicated in AD-DS. More than 80% of those living beyond age 65 are diagnosed with DS-AD. The emergence of DS-AD is thus essentially inevitable in the DS elderly and serves as the leading cause of death. DS-AD thus constitutes the largest population in which a genetic lesion causes AD. An important insight into DS-AD is that increased dose of the gene for APP, present on HSA21, is necessary. Findings in mouse models of DS-AD concur, demonstrating a necessary role for increased APP dose and expression for DS-AD neurodegenerative phenotypes. Studies of DS-AD mouse models have provided important insights, but no current model captures all the pathological features of DS-AD. Three important missing features are: amyloid plaques, congophilic angiopathy, and neurofibrillary tangles (NFTs). We propose to develop and validate a DS-AD model to capture these phenotypes. We will genetically modify the TcMAC21 mouse. This mouse carries an essentially full copy of HSA21 in addition to two copies of homologous mouse chromosomes. To replicate DS-AD amyloid pathology we will humanize the Aβ sequence in mouse APP by crossing with mice in which the Aβ peptide sequence in mouse APP has been humanized, thus conferring a human pattern for processing with increases in APP-C99 and its Aβ products. To introduce human-like tau pathology, including NFTs, the resulting mouse (TcMAC21:APP/hu/hu/hu) will be crossed with mice deleted for mouse tau that express a transgene encoding wild type human Tau. In addition to amyloid and tau pathology we predict the genetically modified TcMAC21 mice will replicate key DS-AD phenotypes. Our hypothesis is that the TcMAC21 mouse will model key pathological features and age-related changes in molecular, cellular and circuit function characteristic of DS-AD. In the R61 Phase: Specific Aim 1 (Project Years 1-3), we will demonstrate feasibility and scale of use, and internally validate it by documenting measures of molecular, cellular, and synaptic age-related phenotypes characteristic of DS-AD with rigor, precision, reliability, and sensitivity, and dependence on APP gene dose. Go/NoGo criteria must be satisfied for moving to the R33 Phase: Specific Aim 2 (Project Years 4,5) in which we will externally validate, through demonstrations of : face validity: 1) measures of cognition; 2) clinical biomarkers, including Aβ42, Aβ40, p-tau species and NFL; construct validity: 1) presence and structure of amyloid plaques and congophilic angiopathy; 2) aggregates of phosphorylated tau; 3) neuroinflammation, including changes in microglia and astrocytes; 4) deficits in synapse number and function; 5) neuron loss; and 6) transcriptomic/genomic signatures; and predictive validity: 1) demonstrate that redu...

## Key facts

- **NIH application ID:** 10973514
- **Project number:** 1R61NS138830-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** William C Mobley
- **Activity code:** R61 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,698,323
- **Award type:** 1
- **Project period:** 2024-08-15 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10973514

## Citation

> US National Institutes of Health, RePORTER application 10973514, Develop and Validate a Mouse Model for Alzheimer Disease in Down Syndrome (1R61NS138830-01). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10973514. Licensed CC0.

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