It is estimated that more than 10% of the 1.1 million HIV positive patients in United States will be over 65 years old in less than ten years, a critical stage in life where the the risk for developing Alzheimer?s disease (AD) increases. Earlier results from clinical studies showed several abnormalities including difficulties with memory, thinking, and reasoning become more common in older HIV positive patients, implying that their risk factors may be elevated when compared with their HIV negative counterparts. This notion brings up the concept that HIV infection, even in patients whose virus is well controlled by antiretroviral therapy (ART), may be more prone to developing neurodegenerative disorders including AD. Considering the inability of ART to effectively suppress expression of viral proteins, including HIV Tat, which is a profoundly neurotoxic protein, we envision a scenario in which, by dysregulating the protein quality control (PQC) pathway, Tat may perturb homeostasis of key proteins associated with the pathogenesis of AD and set the stage for the development of disease. Several data from our and other laboratories support this concept. First, we demonstrated that Tat inhibits expression of BAG3, a co-chaperone/partner of HSP70 that is involved in the removal of dysfunctional and obsolete organelles including mitochondria through a process called mitophagy, and participates in autophagy and clearance of damaged and misfolded proteins by the protein quality control (PQC) pathway. Second, activation of BAG3 is concurrent with a decrease in the level of phosph-tau and an increase in the clearance of tau in neuronal cells. Third, soon after destabilization of microtubules, tau associates with Hsp70/Hsc70, a key partner of BAG3. Fourth, induction of Tat in the brains of transgenic animals increases accumulation of phospho-tau. Thus, Tat- mediated reduction in the level of BAG3 may have a damaging effect on neuronal cells by interrupting the process that ensures intracellular removal of the toxic from of tau, yet maintains the healthy species of tau that is critical for neuronal cell function. Hyper-phosphorylation of tau, which contributes to its misfolding and toxicity, may be attributed to Tat via induction of ROS, ER stress, and mitochondrial dysfunctionality. The latter is of particular interest as truncated tau has been implicated in dysregulation of mitochondrial dynamics and healty energy metabolism. These observations prompted us to hypothesize that, on one hand, Tat impacts the quality and concentration of proper levels of functional tau and the clearance of its toxic form by suppressing expression of BAG3, and on the other hand, Tat contributes to the generation of the toxic tau and dysfunctionality of bioenergetic pathways and mitochondria by inducing stress conditions in cells. To examine this model, we will employ in vitro primary neuronal cultures, ex vivo animal brain tissue, and an in vivo animal model to unravel the underlying molecular basis of HIV-1/Tat-induced perturbation of PQC and homeostasis of tau in neuronal cell function.
Accumulation of toxic proteins in the brain is involved in neurodegenerative diseases such as Alzheimer's Disease (AD). A similar problem can be seen due to stress induced by HIV-1 infection that affects the brain, even in patients whose disease is well controlled with antiretroviral therapy. We will investigate the molecular pathways that regulate clearance of toxic proteins and how they become dysregulated in the aging brain of AD and in HIV-1 brains by examing cross-talk between the HIV-1 Tat protein and the AD tau protein by focusing on the cellular protein, BAG3, that regulates protein quality control and mitochondrial function in neuronal cells. The outcome of these studies will provide important information regarding the pathway by which HIV-1 disrupts interconnected neuronal circuits at the molecular level, which, in turn, coordinately impacts the dysfunctionality of neuronal cells in HIV-1 patients in the aging brain.
