17α-estradiol and sex-differences in HAND with methamphetamine - 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 determined using in vitro and in vivo models. Results of these studies will help in understanding better sex-differences in HAND in the context of misuse of methamphetamine and may provide a solid mechanistic basis for the development of 17α-E2-based therapies against HAND. Thus, our proposed studies are responsive to NOT-DA-21-020 (Evaluation of sex differences on HIV-associated comorbidities in the context of stimulant use).
