# Project 3: Mechanisms of Tauopathies

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $341,742

## Abstract

Project 3: Mechanisms of Tauopathies
Project Leader: Virginia Lee
Project Summary/Abstract
Frontotemporal lobar degeneration (FTLD) with tau pathology (FTLD-Tau) is a group of clinically
heterogeneous neurodegenerative disorders that include progressive supranuclear palsy (PSP), corticobasal
degeneration (CBD), and Pick's disease (PiD). FTLD-Tau diseases are caused by the accumulation of distinct
pathological species or strains of tau (designated PSP-Tau, CBD-Tau, PiD-Tau) and mounting evidence
supports a cell-to-cell spread of pathological tau as a major mechanism of disease that could explain the
progression of FTLD-Tau since Alzheimer's disease (AD), another major tauopathy demonstrated stereotypical
progressive spread of AD tau pathology (AD-Tau) that correlates with progressive dementia. Moreover,
Projects 3 and 4 investigators and others modeled the progressive spread of pathological tau in vitro and in
vivo and demonstrated that tau pathology propagates from cell-to-cell through intercellular transfer of
pathological tau which acts as “seeds” to recruit soluble tau and corrupt it into pathological tau. Thus, Project 3
proposes to test this “transmission” hypothesis and to elucidate the mechanisms of progressive cell-to-cell
spread of pathological tau in FTLD tauopathies. Since FTLD-Tau disorders are clinically diverse, we
hypothesize that misfolded PSP-Tau, CBD-Tau and PiD-Tau represent different tau strains that differ in their
conformations and seeding properties. To test this “strain” hypothesis and to determine the molecular basis
for FTLD-Tau strain diversity, we will purify pathological tau from well characterized CBD, PSP and PiD brains
obtained from Core D that are deeply phenotypically characterized by Cores B-D and Projects 1 & 2 and use
them for in vitro serial amplification experiments to characterize the biochemical and biophysical properties of
tau strains. We will extend these studies to include cell biological research conducted on primary neurons from
non-transgenic (Tg) and tau Tg mice to determine the molecular mechanisms of spread and toxicity. The
effects of genetic factors identified in Project 2 in modifying the transmission of different tau strains will also be
evaluated. Finally, Project 3 will also collaborate with Project 4 by providing well-characterized strain specific
preparations for in vivo studies to test both the misfolded tau transmission and strain hypothesis.

## Key facts

- **NIH application ID:** 9891012
- **Project number:** 5P01AG017586-20
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** VIRGINIA M LEE
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $341,742
- **Award type:** 5
- **Project period:** — → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891012

## Citation

> US National Institutes of Health, RePORTER application 9891012, Project 3: Mechanisms of Tauopathies (5P01AG017586-20). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9891012. Licensed CC0.

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