# Humanized MAPT knockin mouse models for frontotemporal dementia

> **NIH NIH R21** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $468,992

## Abstract

PROJECT SUMMARY/ABSTRACT
 Frontotemporal dementia (FTD) is a common neurodegenerative disorder characterized by progressive
cognitive impairment and functional disability in the elderly group. MAPT (microtubule-associated protein tau)
has been highlighted by its pathogenic mutations in familial FTD patients. In addition, insoluble aggregates of
the tau protein in neurofibrillary tangles are a key pathological hall marker in the brains of Alzheimer’s Disease
(AD) and FTD patients. In order to understand the tau mediated molecular pathogenic mechanisms of
neurodegenerative diseases and dementias, animal models have been generated and characterized. However,
these animal models do not recapitulate the full spectrum and complexity of molecular, cellular, pathological,
behavior, and cognitive features observed in AD and FTD patients, in part because the transgenic mice which
overexpress cDNA or BAC fragments of human MAPT do not represent all molecular features of the human
MAPT in the mouse brain. In this application, we will generate and characterize humanized knockin (KI) mice
with a pathogenic variant of MAPT (P301L) seen in FTD to recapitulate the respective pathophysiology of human
patients in the mouse brain. To achieve this goal, first, we will generate novel humanized KI mice in which the
wild-type human genomic region of MAPT or with P301L mutation is inserted as a replacement of an orthologous
gene in the mouse genome of Mapt locus. This KI replacement of the mouse genomic region with the human
genomic region will express all alternative mRNA and protein isoforms of human wild-type mutant tau under the
endogenous mouse Mapt promoters. Second, we will conduct molecular characterization of hMAPT-P301L KI
mice to examine the spatial and temporal expression profile of human tau in the brains. We will also perform
neuropathological analyses of neuronal survival, tau pathology, and behavioral analyses in hMAPT-P301L KI
mice. The completion of these studies will provide an invaluable tool to investigate the molecular disease
mechanism of MAPT in AD and FTD.

## Key facts

- **NIH application ID:** 10303887
- **Project number:** 1R21NS119990-01A1
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Jongkyun Kang
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $468,992
- **Award type:** 1
- **Project period:** 2021-08-01 → 2023-11-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10303887

## Citation

> US National Institutes of Health, RePORTER application 10303887, Humanized MAPT knockin mouse models for frontotemporal dementia (1R21NS119990-01A1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10303887. Licensed CC0.

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