Executive Function Impairments in HAND and Aging

Project Summary: With the great success of combination antiretroviral therapy (cART), older adults (>50 years of age) now account for 30–50% of HIV-1 seropositive individuals in high-resource countries; a prevalence that is expected to reach approximately 73% by 2030. Critically, older HIV-1 seropositive individuals exhibit a higher frequency of neurocognitive impairments (NCI) relative to their younger counterparts. Neurological complications of HIV infection are the biggest challenge facing HIV researchers, but currently, there are no efficacious treatments for HIV-1-associated neurocognitive disorders (HAND). An innovative regenerative “dendritic spine-targeted” therapeutic approach is proposed to address the neuropathologic hallmark of HAND: synaptodendritic neuronal injury. The hypothesis is that a regenerative “dendritic spine-targeted” approach will alter the longi- tudinal trajectory of HAND (i.e., delay progression of NCI) by restoring synaptodendritic integrity via the NogoA-NgR3/PirB-RhoA signaling pathway. The specific aims are: 1) To establish efficacious “dendritic spine-targeted” therapeutics to address HIV-1-induced synaptodendritic loss and spine dysmorphol- ogy. Factorial design experiments will establish neurorestoration at the synaptic level following treatment with the promising isoflavandiol estrogen S-Equol (SE) as well as a specific estrogen β-receptor agonist (SERBA, i.e., AC-186) in sex-specified brain cell cultures. Given the well-established role of the NogoA-NgR3/PirB-RhoA signaling pathway in synaptic function and dendritic spine growth/retraction, we will employ pharmacological and molecular approaches to investigate whether this pathway mechanistically underlies neurorestoration. 2) To establish the in vivo efficacy of SERBAs to alter the longitudinal trajectory of HAND in the HIV-1 Tg rat. We will promote restoration of neurocognitive function with SERBA therapy (initially SE, a metabolite produced via the gut microbiome following ingestion of soy isoflavone daidzein). Having utilized cross-sectional studies to optimize the treatment conditions of SE to mitigate NCI, we are poised to establish the in vivo efficacy of SE to alter the progression to NCI using a longitudinal design; the factor of biological sex is integral to the experimental design. 3) To establish in vivo the neural mechanism by which SERBAs exert their therapeutic effects. Using a time-sequential longitudinal experimental design, we will examine the regenera- tion of synaptodendritic integrity in pyramidal neurons of the medial prefrontal cortex (mPFC) and medium spiny neurons (MSN) of the nucleus accumbens following SERBA therapy. Using in vivo pharmacological and molecular approaches, the NogoA-NgR3/PirB-RhoA signaling pathway will be examined to establish the underlying neural mechanism. With recently established models, methodological advances, proof-of-concept publications, and new preliminary data, we are in a unique position to critically test: 1) the efficacy of SERBAs to alter the longitudinal trajectory of NCI, and 2) the neural mechanism by which SE exerts its therapeutic effects. Notably, SE is a dietary metabolite affording high translational relevance and promising clinical utility.