# Reversal of Tau Pathology to Rescue Serotonergic Function in Early Alzheimer’s Disease

> **NIH NIH F32** · UNIVERSITY OF IOWA · 2024 · $76,828

## Abstract

Project Summary/Abstract
Alzheimer’s disease and its related dementias (ADRD) are associated with high rates of neuronal death in
affected areas, but little is known about the ability of the brain to recover following therapeutic intervention.
ADRD are characterized by protein deposits consisting of beta-Amyloid peptide and microtubule-associated
protein tau. Tau pathology develops independently of beta-Amyloid deposits, and removal of beta-Amyloid
alone is not sufficient to reduce cognitive decline in mice. The dysfunction of tau is characterized by an
abnormal state of hyper-phosphorylation (P-tau), induced via a plethora of kinase pathways. This P-tau
disrupts cellular function by sequestering other microtubule-associated proteins, directly destabilizing
microtubules, and binding normal tau to form paired helical filaments (PHF-tau). Turnover of the tau protein is
decreased in this pathology, as PHF-tau is resistant to neuronal proteases and degradation by ubiquitination.
In vitro dephosphorylation of P-tau by the phosphoprotein phosphatase PP2A induces dissociation of PHF-tau
and restores susceptibility of tau to protease digestion. PP2A activity and expression is diminished in neurons
exhibiting P-tau pathology. Preliminary data from our lab indicate that direct delivery of PP2A DNA to the
dorsal raphe nucleus (an early presenter of tau pathology) is sufficient to decrease P-tau in ADRD-model mice.
To date, no studies have used targeted reversal of tau pathology at different disease-progression stages to
investigate ADRD treatment outcomes. This proposal will investigate the reversal of P-tau pathology in
serotonergic neurons, to determine any rescue of function or mitigation of P-tau propagation. These findings
will further the understanding of early Alzheimer’s Disease, and may identify a clinically-relevant therapeutic
intervention. Additionally, this fellowship training plan gives high priority to the professional development and
research training of the fellowship recipient. This research training will take place in a highly collaborative and
interdisciplinary laboratory setting within the University of Iowa’s department of Neuroscience and
Pharmacology.

## Key facts

- **NIH application ID:** 10902655
- **Project number:** 1F32AG084196-01A1
- **Recipient organization:** UNIVERSITY OF IOWA
- **Principal Investigator:** Louis Kolling
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,828
- **Award type:** 1
- **Project period:** 2024-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10902655

## Citation

> US National Institutes of Health, RePORTER application 10902655, Reversal of Tau Pathology to Rescue Serotonergic Function in Early Alzheimer’s Disease (1F32AG084196-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10902655. Licensed CC0.

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