# Evaluating the p-Tau inhibition and neuroprotective effects of sAPPalpha using brain permeable small molecules

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $390,000

## Abstract

PROJECT SUMMARY/ABSTRACT
We previously reported (2) on the soluble amyloid precursor protein alpha (sAPPα)-enhancing effects of
tropisetron (F03). Highly brain-permeable F03 is approved in 49 countries for the treatment of post-operative
nausea and vomiting (PONV) and is a multifunctional ligand: it is a potent 5-HT3 serotonin receptor (5-HT3R)
antagonist (Ki ~ 3 nM), a partial α7 nicotinic acetylcholine receptor (α7nAChR) agonist (Ki ~ 450 nM), and binds
to the extracellular domain of amyloid precursor protein (eAPP). In our studies, we found F03 increases sAPPα
and also significantly decreases the phospho-tau (p-tau)/total tau (t-tau) ratio in two Alzheimer's disease (AD)
mouse models. We show that F03 can also reduce corticotropin-releasing factor (CRF) induced p-tau/tau
increase in vitro. Hyperphosphorylation of tau leads to toxic tau oligomers and ultimately formation of
neurofibrillary tangles (NFTs) in AD brain and is closely correlated with cognitive decline (34); thus, decreasing
tau phosphorylation is a critical target for new therapeutic approaches for AD and tauopathies. Based on reports
that sAPPα reduces the p-tau/t-tau ratio through suppression of activity of the kinase GSK3β (9), we plan to
assess the ability of our sAPPα enhancers to reduce the p-tau/t-tau ratio in vitro and in vivo. A key goal of the
project is to identify optimized small molecule sAPPα-enhancing, p-tau/t-tau lowering compounds that improve
cognition in murine AD models, for further development as a novel therapy for AD. An additional goal would be
to elucidate the underlying mechanism of action (MOA) of sAPPα enhancement and related reduction in the p-
tau/t-tau ratio. In Aim 1, we would test F03 and analogs we have in-hand as well as new analogs from Aim 2 in
SH-SY5Y cells and 3xTg-AD primary neurons to establish EC50s for sAPPα enhancement and p-tau/t-tau
decreases. Prioritized compounds would be evaluated for receptor binding and APP binding. Tertiary testing will
be in induced pluripotent stem cell (iPSC)-derived neurons from AD subjects and includes synaptic spine density
quantification. In Aim 2, medicinal chemistry would be used to design new chemical entity (NCE) analogs in a
iterative fashion with receptor and APP binding along with enhanced drug-like properties and oral brain
permeability. In Aim 3, ADME studies on analogs include solubility, microsomal stability, protein binding, parallel
artificial membrane permeability assay (PAMPA) analysis, and in vivo pharmacokinetics (PK). Optimal
candidates would undergo safety (including hERG) and off-target panel profiling along with analyses of effect on
other kinases and of tau phosphorylation sites. In Aim 4 in vivo testing, including acute studies on select
candidates to evaluate effect on intracerebroventricular (ICV) delivered CRF induced p-tau/t-tau increases in
brain in 3xTg-AD mice. Active candidates would be tested in chronic 4-week efficacy studies in 3xTg-AD and
ApoE4-5XFAD AD model mice. Readout...

## Key facts

- **NIH application ID:** 10690009
- **Project number:** 5R01AG073377-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Varghese John
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2022-09-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10690009

## Citation

> US National Institutes of Health, RePORTER application 10690009, Evaluating the p-Tau inhibition and neuroprotective effects of sAPPalpha using brain permeable small molecules (5R01AG073377-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10690009. Licensed CC0.

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