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Int J Clin Exp Pathol 2(5),433-443;2009

Original Article
HIV-1 Tat Contributes to Alzheimer’s Disease-like Pathology in PSAPP Mice

Brian Giunta, Houyan Hou, Yuyan Zhu, Elona Rrapo, Jun Tian, Mori Takashi, Deborah Commins, Elyse Singer, Johnny He, Francisco
Fernandez and Jun Tan

Department of Psychiatry and Behavioral Medicine, Neuroimmunology Laboratory, University of South Florida College of Medicine, Tampa,
Florida 33613, USA; Rashid Laboratory for Neurodevelopmental Biology, Department of Psychiatry and Behavioral Medicine, University of South
Florida College of Medicine, Tampa, Florida 33613, USA; Institute of Medical Science, Saitama Medical School, 1981 Kamoda, Kawagoe,
Saitama, 350-8550, Japan; Department of Pathology, University of Southern California University Hospital, Los Angeles, CA 90095, USA;
National Neurological AIDS Bank, University of California, Los Angeles, CA 90095, USA and Departments of Microbiology and Immunology and
the Walther Cancer Institute, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA

Received 27 January 2009; Accepted and Available online 30 January 2009

Abstract: Prevalence of HIV-associated cognitive impairment is rising. Amyloid-beta (A-beta) plaque deposition in the brain may be a
contributing factor as epidemiological data suggests significant numbers of long-term HIV survivors are at elevated risk of developing
Alzheimer’s disease (AD). HIV-1 Tat-induced A-beta deposition, tau phosphorylation, and subsequent neuronal death could be risk factors for
subsequent AD and/or HIV-related cognitive impairment. To mimic this clinical condition, we generated mice with HIV-1 Tat-induced AD-like
pathology. We first performed a short-term Doxycycline (dox) dosing (54, 108, and 216 mg/kg/day) study in transgenic mice whose astrocytes
express HIV-1 Tat via activation of a GFAP/dox-inducible promoter. After one week, mouse brains were examined histologically and the
expression of Bcl-xL, Bax, and phospho-tau was investigated by Western blotting. We next cross-bred these mice with the PSAPP mouse
model of AD. To simulate chronic Tat secretion over periods longer than one week, we used an optimized dose of 54 mg/kg/day on a bi-weekly
basis over three months; based on the initial dose ranging study in the Tat transgenic mice. This was followed by antisera detection of A-beta,
and Western blot for phospho-tau, Bcl-xL, and Bax. Tat significantly induced neuron degeneration and tau phosphorylation in Tat transgenic
mice, dox dependently (P<0.001) with the most robust effects at the 216 mg/kg/day dose. In the long term study, similar effects at the chronic 54
mg/kg/day dose were observed in PSAPP/Tat mice induced with dox. These mice also showed significantly more A-beta deposition (P < 0.05),
neurodegeneration, neuronal apoptotic signaling, and phospho-tau than PSAPP mice (P < 0.05). In conclusion, HIV-1 Tat significantly
promotes AD-like pathology in PSAPP/Tat mice. This model may provide a framework in which to identify new mechanisms involved in
cognitive impairment in the HIV infected population, and possible treatments. Additional works will be needed to fully characterize the
mechanism(s) of HIV- induced amyloid deposition, and also to uncover viral mechanisms promoting AD-like pathology in general.

Key Words: HIV-1, Tat, PSAPP, Alzheimer’s, Dementia, beta-amyloid

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Address all correspondence to: Brian Giunta, M.D., M.S., Director, Neuroimmunology Laboratory, Department of Psychiatry & Behavioral
Medicine, University of South Florida College of Medicine, MDC 102, Tampa, FL 33613. Tel: 813-974-0616; Fax: 813-974-1130; Email: