# Selective targeting pathological tau signaling in AD and related dementia

> **NIH NIH R21** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2020 · $439,725

## Abstract

Titre:
Selectively targeting pathological tau signaling in AD and related dementia
Abstract
Tauopathies contribute to multiple, devastating neurodegenerative disorders, including Azheimer's disease and
related dementia (ADRD), Fronto-Temporal lobe Dementia (FTD), and Chronic Traumatic Encephalopathy
(CTE), for which there are no effective therapies. Although each tauopathy has a disease specific phenotype,
histological presentation, morphology, and neurological presentation, all are associated with misfolded tau and
altered phosphorylation leading to a gain of toxic function. The search for a common pathogenic mechanism has
been hindered by this clinical diversity. However, recent findings provide new insight into tau pathology. The first
is identification of conformation specific tau antibodies that recognize different pathological forms of tau,
suggesting conformational diversity within the tauopathies. This was corroborated by our recent identification of
a novel feature: Exposure of an N-terminal sequence that is sequestered in non-pathogenic tau. This 17 amino
acid domain comprises a Phosphatase Activation Domain (PAD) and acts as biologically active motif that is
necessary and sufficient to activate a signaling pathway involving protein phosphatase 1 (PP1) and glycogen
synthase kinase 3 β (GSK3β) providing therefore a molecular basis for altered kinase activities in AD and
tauopathies. Interestingly, this PAD region sequestered in normal brain, is aberrantly displayed in all pathological
forms of tau examined to date and is a necessary component of at least two forms of tau toxicity: inhibition of
fast axonal transport and cell toxicity in culture. Therefore, PAD domain represents a novel attractive target for
small molecule therapeutics to treat tauopathies and ADRD. The monoclonal antibody (TNT1), specific to the
Tau-PAD epitope, blocks toxic effects of pathogenic tau. A small molecule that can inhibit the PAD/TNT
protein-protein interaction can theoretically inhibit the actions of pathogenic Tau; and by binding to the PAD
domain can be developed as a radiotracer to map disease progression. The phenotypic effect can be shown
in rescue of axonal transport in squid axons. Aim 1) To identify small molecules hits that inhibit PAD/TNT1
interaction by selectively binding to PAD; Aim 2) Limited med chem hit optimization and phenotypic assay
development to identify an in vitro chemical probe for future development as therapeutic or radiotracer.

## Key facts

- **NIH application ID:** 10128532
- **Project number:** 1R21AG067772-01A1
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** SCOTT THOMAS BRADY
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $439,725
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128532

## Citation

> US National Institutes of Health, RePORTER application 10128532, Selective targeting pathological tau signaling in AD and related dementia (1R21AG067772-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128532. Licensed CC0.

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