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.
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|Giunta, Brian; Hou, Houyan; Zhu, Yuyan et al. (2010) Fish oil enhances anti-amyloidogenic properties of green tea EGCG in Tg2576 mice. Neurosci Lett 471:134-8|
|Smith, Adam; Giunta, Brian; Bickford, Paula C et al. (2010) Nanolipidic particles improve the bioavailability and alpha-secretase inducing ability of epigallocatechin-3-gallate (EGCG) for the treatment of Alzheimer's disease. Int J Pharm 389:207-12|
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|Rrapo, Elona; Zhu, Yuyan; Tian, Jun et al. (2009) Green Tea-EGCG reduces GFAP associated neuronal loss in HIV-1 Tat transgenic mice. Am J Transl Res 1:72-9|
|Giunta, Brian; Hou, Houyan; Zhu, Yuyan et al. (2009) HIV-1 Tat contributes to Alzheimer's disease-like pathology in PSAPP mice. Int J Clin Exp Pathol 2:433-43|
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