# Sigma-1 Receptor Radioligand for Translational Research in Alzheimer's Disease

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $824,959

## Abstract

Project Summary/Abstract
In this grant application we propose to develop and validate an optimal 18F-labeled sigma-1 (σ1) receptor
radioligand for translational research in Alzheimer's disease (AD) to further elucidate the role of σ1 receptor in
AD pathogenesis and progression, to probe longitudinal changes in σ1 receptor in AD animal models, along
with the synapse biomarker synaptic vesicle protein 2A (SV2A), and AD pathologic biomarkers b-amyloid (Ab)
and tau, and to explore the potential of σ1 receptor imaging for early diagnosis of AD.
AD is a progressive degenerative disorder that afflicts 6 million people in the USA. From a diagnostic
perspective, AD is increasingly viewed along a continuum from preclinical AD, to mild cognitive impairment
(MCI), and to AD-dementia. The clinical dementia of AD is coupled to a distinct pathology, with plaques
composed of b-amyloid (Ab), neurofibrillary tangles of hyperphosphorylated tau protein, and synaptic loss.
However, the molecular mechanism(s) of AD pathogenesis is complex and remains elusive. Several
hypotheses have been put forward, including the b-amyloid hypothesis, the misfolded tau protein hypothesis,
the cholinergic hypothesis, and the involvement of oxidative stress and calcium dyshomeostasis. Before the
accumulation of plaques and tangles, the biochemical and morphological changes, such as altered calcium,
cholesterol, and lipid metabolism, altered mitochondrial dynamics, and reduced bioenergetic interaction, are all
closely associated with functions localized to the mitochondria-associated endoplasmic reticulum (ER)
membranes (MAMs). The σ1 receptor is situated at the MAM. The most recent research has located the
earliest Ab generation in AD to neurons in the MAM, and its critical regulation by the σ1 receptor, thereby
confirming the central role of σ1 receptor in AD pathogenesis. As such the σ1 receptor is considered an
important target for AD therapeutic development. As a surrogate marker for mitochondria function and
regulator of Ab production on the MAM, it also holds great promise as a biomarker for diagnosis of AD at its
earliest stage.
 The research proposed in this application will bridge an important gap in the understanding of the σ1 receptor
in AD pathogenesis and progression by leveraging the unique expertise and experience at Yale in novel PET
radioligand development, AD mechanism study, and therapeutic target identification. Investigation of the σ1
receptor in AD animal models longitudinally in relation to biomarkers for synaptic density, Ab, and tau, is a
natural extension of our ongoing research. When carried to completion, this project will provide further insights
into the etiology of AD, and help identify a most sensitive and effective biomarker for early AD diagnosis, and
for monitoring of disease progression and the efficacy of emerging AD therapies.

## Key facts

- **NIH application ID:** 10586550
- **Project number:** 1R01AG076681-01A1
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** YIYUN HENRY HUANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $824,959
- **Award type:** 1
- **Project period:** 2023-09-01 → 2028-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586550

## Citation

> US National Institutes of Health, RePORTER application 10586550, Sigma-1 Receptor Radioligand for Translational Research in Alzheimer's Disease (1R01AG076681-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10586550. Licensed CC0.

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