# Project 4: Pathologic Tau Strains Underlying FTLD-Tau Variants

> **NIH NIH P01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $351,101

## Abstract

PROJECT 4: Pathologic Tau Strains Underlying FTLD-Tau Variants
Project Leader: John Q. Trojanowski; Co-Leader: Virginia M.-Y. Lee
Project Summary/Abstract
 Dementia due to frontotemporal degeneration (FTD) is nearly as common as Alzheimer's disease (AD) in
patients <65 of age. FTD results in frontotemporal lobar degeneration (FTLD) and ~95% of FTLD is due to tau
(FTLD-Tau) or TDP-43 (FTLD-TDP) inclusions. FTLD-Tau and FTLD-TDP account for ~45% and ~50% of
FTLD, respectively, and ~5% is due to FUS pathology (FTLD-FUS) or other rare forms of FTLD. However,
25% of clinical FTD is due to atypical AD. FTLD-Tau syndromes include progressive supranuclear palsy (PSP),
corticobasal degeneration (CBD) and Pick's disease (PiD) and other more rare variants. Although the precise
toxic species of pathological tau are unknown, the stereotypical progression of AD tau pathology suggested the
spread of an unknown pathogen which was identified by demonstrating that extracts of different tauopathy
brains injected into tau transgenic (Tg) mice induced distinct tauopathies. Indeed, the pathological features of
the tau inclusions induced by extracts from PSP, CBD, PiD and AD brains correspond to the neuronal and glia
tau pathology seen in each disorder. Thus, we hypothesize that tau pathology in CBD (CBD-Tau), PSP (PSP-
Tau) and PiD (PiD-Tau) represent different strains of pathological tau that account for the clinical and
pathological heterogeneity of FTD tauopathies. Further support for this has come from Projects 3 and 4 in this
Program Project Grant (PPG) by demonstrating that pre-formed fibrils (PFFs) assembled from recombinant
human tau were sufficient to induce tau pathology in tau Tg mice overexpressing mutant human (P301S) tau
(PS19 line) and that injections of enriched CBD-Tau or AD-Tau into the brains of PS19 mice induced CBD-like
or AD-like tau pathology. Moreover, the spread of tau pathology in tau PFF and AD-Tau injected PS19 mice
followed the neuroanatomical connectome of the injection sites which differed from the spread of glial tau
pathology induced by CBD-Tau. Finally, injections of AD-Tau and tau PFFs resulted in neuron loss, which was
not seen in the CBD-Tau injected PS19 mice. Moreover, diverse manifestations of FTLD-Tau variants also
could reflect the differential effects of genetic modifiers of tau pathology discovered by Project 2 in this PPG
funding cycle. Taken together, these data support our hypothesis that CBD-Tau, PSP-Tau, PiD-Tau and AD-
Tau represent different pathological tau strain that act in concert with genetic modifiers of tau pathology. Thus,
Project 4 builds upon these remarkable new insights to test the hypothesis that distinct clinicopathological
tauopathy variants are due to different strains of pathological tau in association with genetic modifiers of tau
pathology in patient oriented studies to stage tau pathology in autopsy confirmed CBD, PSP and PiD as well as
in experimental studies of CBD-Tau, PSP-Tau and PiD-Tau in a v...

## Key facts

- **NIH application ID:** 9891013
- **Project number:** 5P01AG017586-20
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** JOHN Q. TROJANOWSKI
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $351,101
- **Award type:** 5
- **Project period:** — → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891013

## Citation

> US National Institutes of Health, RePORTER application 9891013, Project 4: Pathologic Tau Strains Underlying FTLD-Tau Variants (5P01AG017586-20). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9891013. Licensed CC0.

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