Brian N. Giunta, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): This applications broad-long term objectives are to train in the applicant in laboratory techniques aimed at modeling/treating neurodegenerative disease. These works will be used in the future to solve an existing health care problem: the lack of current prophylactics or treatments for patients who have HIV-associated dementia (HAD); a neuropsychiatric disorder which has become a chronic disease due in large part to extension of patient life spans by highly active anti-retroviral therapy (HAART). Alzheimer's disease (AD) - like pathology in the form of toxic A(3/(3-amyloid brain deposition is a common feature of HAD, and past works as well as our preliminary data indicate a direct role for HIV-1 Tat inhibition of microglial phagocytosis of Ap peptide. Indeed it is predicted that in the future there will be a large population of HIV infected patients with comorbid AD. To study the effects of chronic HAD-like brain Tat secretion on amyloid beta formation, the following specific aims have been developed. Specific Aim (1) focuses on the creation of a novel mouse model of HAD with AD-like features. Given that HIV-1 Tat inhibits microglial uptake of A(3 (a process augmented by IFN-gamma) and the high prevalence of amyloid brain deposition in the HIV infected population, we propose to cross two previously validated AD (PSAPP mice) and HAD (GT-tg mice) mouse models. PSAPP mice develop AD-like A|3 deposits and associated inflammation while GT-tg mice demonstrate chronic brain HIV-1 Tat expression. We hypothesize this chronic HIV-1 Tat secretion will cause an early onset and increased level of A(3/(3-amyloid deposits in the brain parenchyma of PSAPP/GT-tg mice compared to PSAPP mice and littermate controls. Following behavioral testing, the AJ31-40 and A(31- 42 species will quantified in brain via fluorescence microscopy as well as western blot analysis. Compact amyloid deposits will be detected with Congo red. Apoptotic neurons, synaptic density, neuron counting, morphometric analysis of hippocampal neurons, and inflammatory markers will be quantified as well. Aim (2) tests EGCG as an intervention in vivo in the GT-tg/PSAPP mouse model. We plan to validate in vivo whether EGCG treatment can oppose Tat's effect on the above endpoints in PSAPP/GT-tg mice by intraperitoneally administering EGGG, in prophylactic and therapeutic paradigms. It is hypothesized that EGCG will confer a marked attenuation of the above described pathological end-points in PSAPP/GT-tg mice. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): The cost of the rapid scale-up in prescribing highly active antiretroviral therapy (HAART) for HIV has been significant in terms of side-effects related to brain aging (Heaton et al., 2011; Green et al., 2005; Giunta et al., 2011). There is a need to phase in less toxic HAART regimens. We designed an experiment to understand the interactions between brain aging, HIV-1 Tat protein, and the known cognitive side-effects imparted by chronic HAART (Ciccarelli et al., 2011). We preliminarily found efavirenz (EFV)/lamivudine (3TC)/zidovudine (AZT), a commonly used HAART regimen, promoted ROS production, BACE1 expression, and A??generation both in vitro and in vivo in Tg2576 amyloid depositing mice. This HAART regimen significantly inhibited microglial phagocytosis of A??1-42 peptide as well. Regarding these outcomes, EFV was most potent while AZT was least potent. Additionally we have found that HIV-1 Tat protein inhibits microglial phagocytosis of A?? peptide (Giunta et al., 2008a) and that it contributes to aging pathology in HIV-1 Tat/PSAPP transgenic mice (Giunta et al., 2009). Here we plan to characterize neurocognition, and advanced brain aging pathology in HIV-1 Tat /PSAPP mice chronically treated with HAART. EFV/3TC/AZT should lead to advanced neurocognitive deficits in these mice by 12 months of age that should be synergistically enhanced by brain HIV-1 Tat expression which that can be correlated with elevations in A??1-42/?-CTF, compared to control, EFV, AZT, or 3TC treated mice. This will allow us to isolate which antiretroviral(s) in this commonly used regimen are most neurotoxic during chronic administration. We expect that other indicators of this will outcome will include elevations of AD-like hyperphosphorylated tau, pro-inflammatory cytokines, and dysregulation of microglial A?? phagocytosis, and brain mitochondrial function. This study is expected to describe the long-term consequences of chronic Tat expression with use of a common HAART regimen in terms of advanced brain aging-like neuropathology and cognitive deficits. It should lay the foundation for effective strategies to prevent these interactions between Tat and HAART in the future in the context of a known HAART-mediated pathophysiological mechanism. PUBLIC HEALTH RELEVANCE: Neurocognitive deficits have been associated with decreased adherence among HIV-positive adults. They have also been positively correlated with Tat mediated damage to neurons in the brain as well as chronic HAART use. These trends underscore the need for a better understanding of the impact of how antiretrovirals themselves could promote neurocognitive problems. This is especially true as patients with HIV are now aging; itself being a risk factor neurodegenerative disease such as Alzheimer's. Our proposal addresses these trends by examining the synergistic effects of age, cognitive impairment, and chronic HAART administration on advance brain aging in a transgenic amyloid-beta depositing mouse model.