Frontiers in Aging Neuroscience (May 2022)
HIV-1 gp120 Impairs Spatial Memory Through Cyclic AMP Response Element-Binding Protein
- Jenny Shrestha,
- Jenny Shrestha,
- Maryline Santerre,
- Maryline Santerre,
- Charles N. S. Allen,
- Charles N. S. Allen,
- Sterling P. Arjona,
- Sterling P. Arjona,
- Carmen Merali,
- Ruma Mukerjee,
- Ruma Mukerjee,
- Kumaraswamy Naidu Chitrala,
- Jin Park,
- Asen Bagashev,
- Viet Bui,
- Viet Bui,
- Eliseo A. Eugenin,
- Salim Merali,
- Marcus Kaul,
- Marcus Kaul,
- Marcus Kaul,
- Jeannie Chin,
- Bassel E. Sawaya,
- Bassel E. Sawaya,
- Bassel E. Sawaya,
- Bassel E. Sawaya,
- Bassel E. Sawaya
Affiliations
- Jenny Shrestha
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Jenny Shrestha
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
- Maryline Santerre
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Maryline Santerre
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
- Charles N. S. Allen
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Charles N. S. Allen
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
- Sterling P. Arjona
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Sterling P. Arjona
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
- Carmen Merali
- Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, United States
- Ruma Mukerjee
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Ruma Mukerjee
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
- Kumaraswamy Naidu Chitrala
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
- Jin Park
- Memory and Brain Research Center, Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
- Asen Bagashev
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Viet Bui
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Viet Bui
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
- Eliseo A. Eugenin
- Department of Neuroscience, Cell Biology, and Anatomy, The University of Texas Medical Branch, Galveston, TX, United States
- Salim Merali
- Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, United States
- Marcus Kaul
- Infectious and Inflammatory Disease Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, United States
- Marcus Kaul
- Department of Psychiatry, University of California, San Diego, San Diego, CA, United States
- Marcus Kaul
- Division of Biomedical Sciences, School of Medicine, University of California, Riverside, Riverside, CA, United States
- Jeannie Chin
- Memory and Brain Research Center, Department of Neuroscience, Baylor College of Medicine, Houston, TX, United States
- Bassel E. Sawaya
- Molecular Studies of Neurodegenerative Diseases Lab, Philadelphia, PA, United States
- Bassel E. Sawaya
- Fels Cancer Institute for Personalized Medicine Institute, Philadelphia, PA, United States
- Bassel E. Sawaya
- Department of Neurology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- Bassel E. Sawaya
- 0Department of Cancer and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- Bassel E. Sawaya
- 1Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
- DOI
- https://doi.org/10.3389/fnagi.2022.811481
- Journal volume & issue
-
Vol. 14
Abstract
HIV-associated neurocognitive disorders (HAND) remain an unsolved problem that persists despite using antiretroviral therapy. We have obtained data showing that HIV-gp120 protein contributes to neurodegeneration through metabolic reprogramming. This led to decreased ATP levels, lower mitochondrial DNA copy numbers, and loss of mitochondria cristae, all-important for mitochondrial biogenesis. gp120 protein also disrupted mitochondrial movement and synaptic plasticity. Searching for the mechanisms involved, we found that gp120 alters the cyclic AMP response element-binding protein (CREB) phosphorylation on serine residue 133 necessary for its function as a transcription factor. Since CREB regulates the promoters of PGC1α and BDNF genes, we found that CREB dephosphorylation causes PGC1α and BDNF loss of functions. The data was validated in vitro and in vivo. The negative effect of gp120 was alleviated in cells and animals in the presence of rolipram, an inhibitor of phosphodiesterase protein 4 (PDE4), restoring CREB phosphorylation. We concluded that HIV-gp120 protein contributes to HAND via inhibition of CREB protein function.
Keywords
