# 17α-estradiol and sex-differences in HAND with methamphetamine

> **NIH NIH R01** · UNIVERSITY OF NORTH DAKOTA · 2024 · $444,498

## Abstract

Project Abstract
The pathogenesis of HIV-associated neurocognitive disorders (HAND) in ART era is complex and may result
from low levels of HIV-1 replication/HIV-1 proteins, ART drugs, drug of abuse, and the misuse of stimulants
such as methamphetamine. It is envisioned that combined exposure of these HIV-related factors leads to
reversible synaptodendritic impairment that contribute to the development of HAND. Growing evidence
indicates the existence of sex differences in both HAND and in methamphetamine misuse; Women living with
HIV have greater neurocognitive impairments, and methamphetamine misuse leads to more severe gray
matter damage and cognitive deficits in female. One factor for these sex-differences is estradiol (E2), a major
form of estrogen with two isoforms (17β-E2 and 17α-E2). Although both isoforms are neuroprotective,17α-E2,
the predominant estrogen in the brain, may play an important role in HAND. Significantly, our findings indicate
that endolysosomes represent as critical sites, where 17α-E2, HIV proteins (gp120 and Tat), ART drugs, and
methamphetamine could intersect to affect synaptodendritic impairment and sex-differences in HAND.
Endolysosomes are important for important in modulating neuronal plasticity because their extensive
processes require constant vesicular membrane trafficking to maintain axonal and somatodendritic
membranes. Endolysosome dysfunction resulting from combined exposure of HIV-related factors could lead to
synaptodendritic impairment. Conversely, the endolysosome enhancing effect of 17α-E2 could reverse
synaptodendritic impairment and contribute to sex-differences in HAND. The objective here is to investigate the
role of endolysosomes in synaptodendritic impairment and sex-differences in HAND. We will test the
hypothesis that endolysosome localization of estrogen receptor-α (ERα) is critical for the protective effects of
17α-E2 against endolysosome dysfunction and synaptodendritic impairments resulting from combined
exposure of HIV-related factors (gp120, Tat, ART drugs, and methamphetamine). Guided by our preliminary
findings, our novel hypothesis will be tested by pursuing two specific aims. (1) Determine the role of ERα in the
protective effects of 17α-E2 against endolysosome dysfunction and synaptodendritic impairments, resulting
from combined exposure of HIV-1 proteins (gp120 and Tat), ART drugs, and methamphetamine. (2) Determine
the extent to which 17α-E2 affects cognitive impairment and the development of endolysosome dysfunction
and synaptodendritic impairments in HIV-1 Tg rats exposed with ART drugs and/or methamphetamine. The
proposed work is focused to determine the novel role of 17α-E2 and endolysosomes in sex-differences in
HAND with misuse of methamphetamine. Mechanistically, endolysosomes are critical sites, where 17α-E2, HIV
proteins, ART drugs, and methamphetamine intersect to affect synaptodendritic impairment and sex-
differences in HAND. The therapeutic potential of 17α-E2 will be ...

## Key facts

- **NIH application ID:** 10913617
- **Project number:** 5R01DA059280-02
- **Recipient organization:** UNIVERSITY OF NORTH DAKOTA
- **Principal Investigator:** Xuesong Chen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $444,498
- **Award type:** 5
- **Project period:** 2023-09-01 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10913617

## Citation

> US National Institutes of Health, RePORTER application 10913617, 17α-estradiol and sex-differences in HAND with methamphetamine (5R01DA059280-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10913617. Licensed CC0.

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