Wednesday, April 2, 2025
4/2/2025
pTau-related neuron and cognitive dysfunction in opioid-HIV comorbidity: Longitudinal and functional studies - HIV associated neurocognitive disorder (HAND) affects ~50% of people living with HIV (PWH), and concurrent opioid use disorder (OUD) can enhance symptoms. Since CNS pathology in HIV associated neurocognitive disorder (HAND) bears similarities to Alzheimer’s disease (AD) and other ‘tauopathies’ in which accumulation of abnormally phosphorylated Tau protein (pTau) is considered a critical factor in the development/progression of cognitive symptoms, it is reasonable to think that pTau may have a role in driving cognitive dysfunction in HIV/HAND. Compared to AD, cognitive changes in HAND are measured earlier and only ≤5% result in dementia. While post-mortem studies have documented pTau species within HAND+ and OUD brain tissue, and we see pTau deposition in animal models of HAND/OUD that exhibit cognitive decline, the question of whether pTau triggers deficits in neuron function that underlie HAND/OUD is not clear. The studies proposed here will clarify whether pTau has a causal role. Our preliminary and published work shows that multiple pathologic forms of pTau are present in specific brain regions of a murine model of HAND, and that pTau levels are increased by 2- 8 wks of concurrent morphine exposure. These findings coincide with cognitive issues and motor dysfunction, as well as in situ physiological changes in neurons in specific brain regions, including hippocampus. We propose functional studies to connect these interrelated findings, testing the hypothesis that tau/pTau is a critical driver of cognitive dysfunction in HAND and the exacerbation by opioids. Studies evaluate (i) CA1 pyramidal cell (PC) output; (ii) a CA1 microcircuit of interneurons that are vulnerable to Tat and express µ-opioid receptor. Functional assessments use (i) patch-clamp physiology, and (ii) miniscopes to follow activity of individual neurons for 12 weeks in awake, behaving mice (inscopix.com). Physiological (patch clamp), histological and biochemical damage are evaluated on tissue from individual behaving mice so that all outcomes can be directly correlated. While pTau is elevated in several brain regions, we focus on hippocampus, an area critical to normal cognitive processes which is clearly involved in a multiple conditions of cognitive decline. Two transgenic models of HAND in virally suppressed PWH that exhibit cognitive dysfunction (inducible CNS expression of HIV Tat; Tg26) are used to suggest relative contributions of Tat vs other HIV proteins in HAND. Longitudinal, 12 week studies evaluate gain- (Cre/AAV) and loss-of-pTau function on cognitive behavior and neuron dysfunction/damage in both sexes. The loss-of-pTau studies employ 2 models. The primary model is treatment with TRx023, an anti- pTau drug with significant effects in a Phase III clinical trial (TauRx.com). Because it is given during the disease process it is clinically relevant. The second model, judiciously undertaken based on TRx0237 results, is to create a new line of Tat+ or Tg26 mice crossed with a Tau-deficient transgenic (Tau-/-) that will eliminate Tau/pTau completely and constituitively. Overall, the studies represent a comprehensive approach that tests the role of pTau in HAND/OUD using a design for direct correlations between tissue level damage and cognitive decline.
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