# Effects of opiates on neurons and their impact on HIV neuropathology

> **NIH NIH R01** · DREXEL UNIVERSITY · 2020 · $441,744

## Abstract

Project Summary/Abstract
HIV-associated neurocognitive disorders (HAND) persist in virally suppressed patients. HAND is a
heterogeneous disease that is characterized by chronic low-level inflammation, excitotoxicity, presence of
neurotoxic HIV proteins, altered APP processing, and other factors that aggravate neuronal structure and
function. Opioid use is common among HIV+ patients and thought to contribute to HAND, although this
remains controversial. Studies from the previous funding period suggest that morphine can augment HAND by
altering APP processing through a novel, iron-dependent pathway. Toxic APP cleavage products are known to
reduce dendritic spines in several brain areas, which are critical mediators of learning and memory.
Surprisingly, the effects of APP cleavage products on dendritic spines of the prefrontal cortex (PFC), which is
an area of critical importance to HAND, have not been studied in depth. This project will elucidate the role of
altered APP processing in morphine and HIV-induced neuronal deficits in the PCF. Studies will unravel the
interaction between HIV and Aβ proteins and determine whether morphine can contribute to alteration of APP
processing and spines in HAND. Research in aim 1 will concentrate on the effect of Aβ oligomers on dendritic
spine structure and function in PFC neurons, in the presence and absence of HIV neurotoxins or morphine.
These in vitro and in vivo studies will define meaningful changes in dendritic spine density/morphology/turnover
in PFC neurons, and provide a full assessment of exogenously added Aβ actions in this critical brain area (the
role of endogenous Aβ will be further tested in aim 3). The main goal of aim 2 is to establish the extent to
which µ-opioids can affect amyloidogenesis through modulation of neuronal iron. These mechanistic studies
are based on our recent discoveries suggesting a role for iron in morphine-mediated dendritic spine reduction
in cortical neurons. They are also supported by the finding that endosome deacidification leads to increase of
cytosolic Fe2+ and Aβ. Importantly, cytosolic Fe2+ regulates APP expression whilst endolysosomal pH
modulates protein degradation. In aim 3, we will employ newly generated molecular tools able to shift APP
processing to the α-cleavage pathway or prevent APP cleavage by β-secretases. After functional testing in
primary cultures, the most promising constructs will be expressed in PFC neurons of HAND animal models to
determine how effectively they reduce Aβ levels in the presence of HIV proteins/morphine and if Aβ reduction
contributes to recovery of PFC cognitive tasks. This proposal will shed light on iron-dependent mechanisms of
accelerated cognitive decline in HIV+/opiate abusing subjects, which is becoming increasingly relevant as ART-
treated patients live longer.

## Key facts

- **NIH application ID:** 9891995
- **Project number:** 5R01DA032444-07
- **Recipient organization:** DREXEL UNIVERSITY
- **Principal Investigator:** Olimpia Meucci
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,744
- **Award type:** 5
- **Project period:** 2012-07-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9891995

## Citation

> US National Institutes of Health, RePORTER application 9891995, Effects of opiates on neurons and their impact on HIV neuropathology (5R01DA032444-07). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9891995. Licensed CC0.

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