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, Jun Tan

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33 Scopus citations

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 biweekly 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.

Original languageEnglish
Pages (from-to)433-443
Number of pages11
JournalInternational Journal of Clinical and Experimental Pathology
Volume2
Issue number5
StatePublished - 19 Jun 2009

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Keywords

  • Alzheimer's
  • Beta-amyloid
  • Dementia
  • HIV-1
  • PSAPP
  • Tat

Cite this

Giunta, B., Hou, H., Zhu, Y., Rrapo, E., Tian, J., Takashi, M., Commins, D., Singer, E., He, J., Fernandez, F., & Tan, J. (2009). HIV-1 tat contributes to Alzheimer's disease-like pathology in PSAPP mice. International Journal of Clinical and Experimental Pathology, 2(5), 433-443.