# Therapeutic targeting a membrane estrogen receptor with a novel non-steroidal compound for Alzheimer's disease

> **NIH NIH R56** · OREGON HEALTH & SCIENCE UNIVERSITY · 2022 · $766,929

## Abstract

Effective treatments for Alzheimer's Disease (AD) are still lacking, and drugs that directly target β-amyloid (Aβ)
and hyperphosphorylated Tau (pTau) have been largely unsuccessful. As an alternative, developing drugs that
mitigate downstream neurodegenerative responses (independent of Aβ and pTau) might provide a more
effective therapeutic strategy. Notably, the loss of ovarian steroid production significantly increases the risk of
AD in postmenopausal women, raising hopes that hormone replacement could be used to prevent or treat AD.
Unfortunately, clinical trials found that 17β-estradiol (E2) produced unacceptable side effects (including
increased oncogenic and thrombotic events), and actually increased the risk of dementia in some patients.
More recent trials targeting E2 to a perimenopausal `critical period' had better overall outcomes but still
involved an increased risk for dementia. Likewise, selective estrogen receptor modulators (SERMs) targeting
classical estrogen receptors are equally problematic, as chronic activation of either ERα or ERβ can still result
in hormone-sensitive cancers. In contrast, STX is a novel SERM with unique properties. STX specifically
engages GqMER (Gq-coupled membrane estrogen receptor), which has been shown to confer many of the
neuroprotective benefits of E2 without its side effects. Oral STX readily crosses the blood-brain barrier and can
be safely administered for sustained periods. Moreover, studies using both rodent and primate models of
menopause have shown that STX treatment can rescue homeostatic functions as effectively as E2 without its
side effects (including feminizing effects in males), reflecting the fact that GqMER is expressed by CNS
neurons but not by other cell types in the brain or by peripheral reproductive organs. In cultured hippocampal
neurons, STX was found to protect against the neurotoxic effects of both Aβ and pTau. Preliminary studies
using the 5XFAD model of amyloid pathology indicate that oral STX can also protect against the loss of
cognitive function, acting in part by supporting normal synaptic activity in the brain. Accordingly, we will use this
well-characterized AD model to investigate the neuroprotective mechanism and functional benefits of STX in
three complementary aims. Aim 1 will include a suite of behavioral assays (coupled with postmortem assays
of neuropathology) to determine the beneficial effects of oral STX in protecting against AD-associated
neurodegeneration. Aim 2 will employ electrophysiological protocols in hippocampal slice preparations to
investigate the mechanisms by which STX mitigates the loss of synaptic functions that affect learning and
memory in the AD brain. Aim 3 will use in vivo multiphoton imaging combined with subsequent confocal
methods to analyze the neuroprotective effects of STX on mitochondrial function and synaptic spine integrity in
the 5XFAD mice.

## Key facts

- **NIH application ID:** 10670490
- **Project number:** 1R56AG078220-01
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** PHILIP F COPENHAVER
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $766,929
- **Award type:** 1
- **Project period:** 2022-09-15 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10670490

## Citation

> US National Institutes of Health, RePORTER application 10670490, Therapeutic targeting a membrane estrogen receptor with a novel non-steroidal compound for Alzheimer's disease (1R56AG078220-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10670490. Licensed CC0.

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