scholarly journals HIV and FIV glycoproteins increase cellular tau pathology via cGMP-dependent kinase II activation

2022 ◽  
Author(s):  
Matheus F Sathler ◽  
Michael J Doolittle ◽  
James A Cockrell ◽  
India R Nadalin ◽  
Franz Hofmann ◽  
...  

As the development of combination antiretroviral therapy (cART) against human immunodeficiency virus (HIV) drastically improves the lifespan of individuals with HIV, many are now entering the prime age when Alzheimer's disease (AD)-like symptoms begin to manifest. Hyperphosphorylated tau, a known AD pathological characteristic, has been prematurely increased in the brains of HIV-infected patients as early as in their 30s and is increased with age. This thus suggests that HIV infection may lead to accelerated AD phenotypes. However, whether HIV infection causes AD to develop more quickly in the brain is not yet fully determined. Interestingly, we have previously revealed that viral glycoproteins, HIV gp120 and feline immunodeficiency virus (FIV) gp95, induce neuronal hyperexcitation via cGMP-dependent kinase II (cGKII) activation in cultured hippocampal neurons. Here, we use cultured mouse cortical neurons to demonstrate that HIV gp120 and FIV gp95 are sufficient to increase cellular tau pathology, including intracellular tau hyperphosphorylation and tau release to the extracellular space. We further reveal that viral glycoprotein-induced cellular tau pathology requires cGKII activation. Together, HIV infection likely accelerates AD-related tau pathology via cGKII activation.

Author(s):  
Avindra Nath

It has been nearly three decades since the first descriptions of the neurological comploications of HIV infection. During this period of time there has been tremendous progress in defining the clinical syndromes, modes of diagnosis, detailed pathophysiology and modes of treatment. Many of the dreaded complications are now manageable particularly if diagnosed early. However, neurocognitive impairment associated with HIV infection still remains a significant cause of morbidity and much is needed to control; the effects of the virus on the brain and for the eventual eradication of the virus from the brain reservoir.


Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2842-2848 ◽  
Author(s):  
Y. Taoufik ◽  
O. Lantz ◽  
C. Wallon ◽  
A. Charles ◽  
E. Dussaix ◽  
...  

Abstract Interleukin-12 (IL-12), a cytokine with in vitro and in vivo immunomodulatory effects, is produced mostly by activated monocytes and macrophages. To study the effect of human immunodeficiency virus (HIV) infection on IL-12 production, we investigated the expression of IL-12 at mRNA and protein levels by human monocytes preincubated with HIV-gp120. In these conditions, we show that monocytes have a decreased ability to express IL-12 mRNA subunits and to produce IL-12 p40 and bioactive p70 proteins in response to Staphylococcus aureus strain cowan I (SAC). We showed that in human monocyte cultures, HIV-gp120 induces a significant IL-10 synthesis, which in turn inhibits IL-12 subunits mRNA accumulation and protein secretion after SAC-activation. Similar data were obtained with human macrophages. These results suggest that, during HIV infection, gp120 induces in uninfected monocytes and macrophages IL-10/IL-12 disregulation, which can alter immune response.


PEDIATRICS ◽  
1993 ◽  
Vol 91 (4) ◽  
pp. 742-746
Author(s):  
Wendy G. Mitchell ◽  
Marvin D. Nelson ◽  
Charles F. Contant ◽  
James F. Bale ◽  
Don A. Wilson ◽  
...  

To determine the effects of hemophilia and human immunodeficiency virus (HIV) infection on the nervous system, the authors examined the relationship of brain magnetic resonance imaging (MRI) findings to immunologic function and neurologic examination findings. Baseline examinations included physical and neurologic examination, immunologic and virologic testing, and MRI of the brain. On neurologic examination, muscle atrophy was considered to be related to hemophilia if adjacent joints had arthropathy due to bleeding. Muscle atrophy was considered non-hemophilia-related if unrelated to arthropathy or if muscle atrophy was diffuse. Subjects were boys aged 6 to 19 years, enrolled in a multicenter study of the effects of hemophilia and HIV infection on growth and development, all with congenital coagulopathies requiring factor infusions. Three hundred ten subjects had complete data including neurologic examination, T-cell subsets, HIV antibodies, and MRI. Subjects with HIV infection whose CD4+ counts were <200/µL were compared with subjects with HIV infection and CD4+ counts ≥200/µL and with HIV-negative subjects, all of whom had CD4+ counts >200/µL. MRI studies were normal in 230. Abnormal MRI studies were more frequent in HIV-positive subjects with CD4+ counts <200 (29.4% abnormal compared with 17% in HIV-positive subjects with CD4+ counts ≥200 and 15.3% in HIV-negative subjects). Diffuse atrophy accounted for most of the excess abnormalities in HIV-positive subjects with CD4+ counts <200 (77.3% of abnormal scans). Diffuse atrophy on MRI was associated with decreased muscle bulk on neurologic examination, but not with abnormal tendon reflexes. Four of six subjects with non-hemophilia-related diffuse muscle atrophy had cerebral atrophy on MRI. All 6 were HIV-positive and had CD4+ counts <200. Congenital abnormalities (primarily arachnoid cysts) were present in 12 subjects, not related to HIV or CD4+ status. Acquired focal abnormalities including both old hemorrhagic lesions (12 subjects) and nonhemorrhagic lesions (66 subjects) were equally frequent in HIV-positive and HIV-negative groups and did not differ by CD4+ count. Multifocal white-matter lesions, hyperintense on T2-weighted images, seen in both HIV-positive and HIV-negative subjects, are of uncertain significance. Of the multiple MRI abnormalities found, only diffuse cerebral atrophy appears to be associated with HIV infection, and only in subjects with compromised immunologic function.


2009 ◽  
Vol 102 (2) ◽  
pp. 1160-1171 ◽  
Author(s):  
Ryan Kellogg ◽  
Ken Mackie ◽  
Alex Straiker

Long-term depression (LTD) of synaptic signaling—lasting from tens of minutes to hours or longer—is a widespread form of synaptic plasticity in the brain. Neurons express diverse forms of LTD, including autaptic LTD (autLTD) observed in cultured hippocampal neurons, the mechanism of which remains unknown. We have recently reported that autaptic neurons express both endocannabinoid-mediated depolarization-induced suppression of excitation (DSE) and metabotropic suppression of excitation (MSE). We now report that activating cannabinoid CB1 receptors is necessary for the induction of autLTD. Most surprisingly, CB1 does not induce autLTD via the Gi/o proteins typically activated by this receptor nor with Gs. Rather, the requirements of presynaptic phospholipase C and filled calcium stores suggest Gq. In autLTD, a 3- to 4-min activation of the receptor by the endocannabinoid 2-arachidonoyl glycerol leads to prolonged inhibition while leaving short-term inhibition (e.g., DSE) intact. autLTD requires activation of both metabo- and ionotropic glutamate receptors. autLTD also requires MEK/ERK activation. Under certain conditions, one or more DSE stimuli will elicit autLTD. It is becoming evident that cannabinoids mediate multiple forms of plasticity at a single synapse, stretching temporally from tens of seconds (DSE/MSE) to tens of minutes (autLTD) to hours (CB1 desensitization). Our findings imply a remarkable flexibility for the cannabinoid signaling system whereby discrete mechanisms of CB1 activation within a single neuron yield temporally and mechanistically distinct forms of plasticity.


2001 ◽  
Vol 21 (4) ◽  
pp. 334-343 ◽  
Author(s):  
Carsten Culmsee ◽  
Yuan Zhu ◽  
Josef Krieglstein ◽  
Mark P. Mattson

After a stroke many neurons in the ischemic brain tissue die by a process called apoptosis, a form of cell death that may be preventable. The specific molecular cascades that mediate ischemic neuronal death are not well understood. The authors recently identified prostate apoptosis response-4 (Par-4) as a protein that participates in the death of cultured hippocampal neurons induced by trophic factor withdrawal and exposure to glutamate. Here, the authors show that Par-4 levels increase in vulnerable populations of hippocampal and striatal neurons in rats after transient forebrain ischemia; Par-4 levels increased within 6 hours of reperfusion and remained elevated in neurons undergoing apoptosis 3 days later. After transient focal ischemia in mice, Par-4 levels were increased 6 to12 hours after reperfusion in the infarcted cortex and the striatum, and activation of caspase-8 occurred with a similar time course. Par-4 immunoreactivity was localized predominantly in cortical neurons at the border of the infarct area. A Par-4 antisense oligonucleotide protected cultured hippocampal neurons against apoptosis induced by chemical hypoxia and significantly reduced focal ischemic damage in mice. The current data suggest that early up-regulation of Par-4 plays a pivotal role in ischemic neuronal death in animal models of stroke and cardiac arrest.


2018 ◽  
Vol 11 ◽  
pp. 117863371775268 ◽  
Author(s):  
Luminita Ene

Introduction: Human immunodeficiency virus (HIV) enters the brain early, where it can persist, evolve, and become compartmentalized. Central nervous system (CNS) disease can be attributed to HIV alone or to the complex interplay between the virus and other neurotropic pathogens. Aim: The current review aims to describe the direct impact of HIV on the brain as well as its relationship with other pathogens from a practitioner’s perspective, to provide a general clinical overview, brief workup, and, whenever possible, treatment guidance. Methods: A review of PubMed was conducted to identify studies on neuropathogenesis of HIV in relation to host responses. Furthermore, the interaction between the CNS pathogens and the host damage responses were revised in the setting of advanced and also well-controlled HIV infection. Results: Similar to other pathogens, HIV leads to CNS immune activation, inflammation, and viral persistence. Therefore, almost half of the infected individuals present with neurocognitive disorders, albeit mild. Compartmentalized HIV in the CNS can be responsible in a minority of cases for the dramatic presentation of symptomatic HIV escape. Disruption of the immune system secondary to HIV may reactivate latent infections or allow new pathogens to enter the CNS. Opportunistic infections with an inflammatory component are associated with elevated HIV loads in the cerebrospinal fluid and also with greater cognitive impairment. The inflammatory immune reconstitution syndrome associated with CNS opportunistic infections can be a life-threatening condition, which needs to be recognized and managed by efficiently controlling the pathogen burden and timely balanced combination antiretroviral therapy. Latent neurotropic pathogens can reactivate in the brain and mimic HIV-associated severe neurological diseases or contribute to neurocognitive impairment in the setting of stable HIV infection. Conclusions: As HIV can be responsible for considerable brain damage directly or by facilitating other pathogens, more effort is needed to recognize and manage HIV-associated CNS disorders and to eventually target HIV eradication from the brain.


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