期刊
FRONTIERS IN CELLULAR NEUROSCIENCE
卷 16, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fncel.2022.812887
关键词
HIV gp120; glycolysis; memory; neurons; metabolic reprogramming; advanced glycation end-product
资金
- NIH-NIA [AG054411]
- NIH [NS076402, MH093331]
- [HIV-1 IIIB gp120]
- [HIV-1 JR-CSF Fcgp120]
- [11556]
Patients infected with HIV-1 often suffer from HIV-associated neurocognitive disorders (HAND), such as spatial memory impairments. Research has shown that the HIV-1 protein, gp120, alters cellular metabolism and impairs memory function. By understanding the cellular processes and the proteins involved, potential treatments to prevent or reverse this memory impairment can be explored.
A significant number of patients infected with HIV-1 suffer from HIV-associated neurocognitive disorders (HAND) such as spatial memory impairments and learning disabilities (SMI-LD). SMI-LD is also observed in patients using combination antiretroviral therapy (cART). Our lab has demonstrated that the HIV-1 protein, gp120, promotes SMI-LD by altering mitochondrial functions and energy production. We have investigated cellular processes upstream of the mitochondrial functions and discovered that gp120 causes metabolic reprogramming. Effectively, the addition of gp120 protein to neuronal cells disrupted the glycolysis pathway at the pyruvate level. Looking for the players involved, we found that gp120 promotes increased expression of polypyrimidine tract binding protein 1 (PTBP1), causing the splicing of pyruvate kinase M (PKM) into PKM1 and PKM2. We have also shown that these events lead to the accumulation of advanced glycation end products (AGEs) and prevent the cleavage of pro-brain-derived neurotrophic factor (pro-BDNF) protein into mature brain-derived neurotrophic factor (BDNF). The accumulation of proBDNF results in signaling that increases the expression of the inducible cAMP early repressor (ICER) protein which then occupies the cAMP response element (CRE)-binding sites within the BDNF promoters II and IV, thus altering normal synaptic plasticity. We reversed these events by adding Tepp-46, which stabilizes the tetrameric form of PKM2. Therefore, we concluded that gp120 reprograms cellular metabolism, causing changes linked to disrupted memory in HIV-infected patients and that preventing the disruption of the metabolism presents a potential cure against HAND progression.
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