HIV-1 gp120 impairs spatial memory through CREB
bioRxiv (Cold Spring Harbor Laboratory)(2020)
Abstract
HIV-associated neurocognitive disorders (HAND) remains an unsolved problem in the clinical management of HIV-1 carriers, because existing anti-retroviral therapy while suppressing viral replication, do not prevent neurocognitive impairment (e.g. spatial memory loss). HIV-1 gp120 protein has been proposed to contribute to HAND because it is shed by infected cells and the use of antibodies revealed its presence in cerebrospinal fluid (CSF) even in the combinatory antiretroviral therapy (cART) era. The cyclic AMP response element-binding protein (CREB) has long been known to be a star player in memory. CREB exerts its effect partially through regulating the genes for peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α and brain-derived neurotrophic factor (BDNF). CREB, PGC-1α, and BDNF levels are low in the brains of patients with neurodegenerative diseases and a dearth of either protein is associated with cognitive decline. We have obtained data showing that gp120 contributes to neurodegeneration by altering CREB phosphorylation on serine residue 133 thus disrupting mitochondrial movement and synaptic plasticity leading to spatial memory loss. Inhibition of CREB function was also associated with a decrease of ATP levels and lower mitochondrial DNA copy numbers. Our data was validated in vitro (primary mouse neurons and neuronal cell line, SH-SY5Y) and in vivo (gp120-tg mice and mice injected with gp120). The negative effect of gp120 was alleviated in cells and animals in the presence of Rolipram. Hence, we conclude that HIV-1 gp120 protein contributes to spatial memory impairment via inhibition of CREB protein activity.
* HIV
: Human immunodeficiency virus
HAND
: HIV-associated neurocognitive disorders
CSF
: cerebrospinal fluid
cART
: combinatory antiretroviral therapy
CREB
: cyclic AMP response element-binding protein
PGC-1α
: peroxisome proliferator-activated receptor gamma coactivator
BDNF
: brain-derived neurotrophic factor
OS
: oxidative stress
AD
: Alzheimer’s disease
PD
: Parkinson’s disease
ALS
: Amyotrophic lateral sclerosis
HD
: Huntington’s disease
CRE
: cAMP response elements
IL-10
: interleukin 10
PKA
: protein kinase A
tg
: transgenic
GFAP
: glial fibrillary acidic protein
IF
: immunofluorescence
ROS
: reactive oxygen species
post synaptic density 95
: PSD-95
mtDNA
: mitochondrial DNA
OCR
: oxygen consumption rate
ECAR
: extracellular acidification rate
TCA
: Tricarboxylic acid cycle
MoreTranslated text
AI Read Science
Must-Reading Tree
Example
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
Generate MRT to find the research sequence of this paper
Chat Paper
Summary is being generated by the instructions you defined