Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

Vartak-Sharma, Neha; Nooka, Shruthi; Ghorpade, Anuja

doi:10.1016/j.pneurobio.2016.03.006

Cited by 23 publications

(13 citation statements)

References 313 publications

(388 reference statements)

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“…AEG-1 is also known to exhibit diverse functions by interacting with several cellular proteins in cancer. 32 As AEG-1 can function as a transcriptional coactivator and as a scaffolding protein, we examined whether AEG-1 directly binds to calnexin ( Figure 5l ). Consistent with the confocal analyses, coimmunoprecipitation data confirmed AEG-1 interacted with calnexin in untreated, IL-1 β -, abacavir-, or Th-treated astrocytes ( Figure 5l ).…”

Section: Resultsmentioning

confidence: 99%

HIV-1-associated inflammation and antiretroviral therapy regulate astrocyte endoplasmic reticulum stress responses

Nooka

Ghorpade

2017

Cell Death Discov.

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Antiretroviral (ARV) therapy (ART) has effectively suppressed the incidence of human immunodeficiency virus (HIV)-associated dementia in HIV-1 positive individuals. However, the prevalence of more subtle forms of neurocognitive dysfunction continues to escalate. Recently, endoplasmic reticulum (ER) stress has been linked to many neurological diseases; yet, its role in HIV/neuroAIDS remains largely unexplored. Furthermore, upregulation of astrocyte elevated gene-1 (AEG-1), a novel HIV-1 inducible gene, along with ER stress markers in a Huntington’s disease model, suggests a possible role in HIV-associated ER stress. The current study is focused on unfolded protein responses (UPRs) and AEG-1 regulation in primary human astrocytes exposed to HIV-associated neurocognitive disorders (HAND)-relevant stimuli (HIV-1 virions, inflammation and ARV drugs). Interleukin (IL)-1β and the nucleoside reverse transcriptase inhibitor abacavir upregulated expression of ER stress markers in human astrocytes, including binding immunoglobulin protein (BiP), C/EBP homologous protein (CHOP), and calnexin. In addition, IL-1β activated all three well-known UPR pathways: protein kinase RNA-like ER kinase (PERK); activating transcription factor 6 (ATF-6); and inositol-requiring enzyme 1α (IRE1α). AEG-1 upregulation correlated to ER stress and demonstrated astrocyte AEG-1 interaction with the calcium-binding chaperone, calnexin. IL-1β and abacavir enhanced intracellular calcium signaling in astrocytes in the absence of extracellular calcium, illustrating ER-associated calcium release. Alternatively, calcium evoked in response to HAND-relevant stimuli led to mitochondrial permeability transition pore (mPTP) opening in human astrocytes. Importantly, IL-1β- and abacavir-induced UPR and mPTP opening were inhibited by the intracellular calcium chelation, indicating the critical role of calcium signaling in HAND-relevant ER stress in astrocytes. In summary, our study highlights that ARV drugs and IL-1β induced UPR, AEG-1 expression, intracellular calcium, and mitochondrial depolarization in astrocytes. This study uncovers astrocyte ER stress as a novel therapeutic target in the management of HIV-1-associated neurotoxicity and possibly in the treatment of neuroAIDS.

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Section: Resultsmentioning

confidence: 99%

HIV-1-associated inflammation and antiretroviral therapy regulate astrocyte endoplasmic reticulum stress responses

Nooka

Ghorpade

2017

Cell Death Discov.

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“…Therefore, these results were taken to suggest metabolic abnormalities that occurred without secondary atrophy in the putamen, pallidum, and thalamus. While HIV creates a neurotoxic environment within the CNS leading to cell death and regional atrophy, there are also several consequences of HIV infection which can lead to hypertrophy, including abnormal proliferation of astrocytes (i.e., astrocytosis) [Buffo et al, 2008;Ton & Xiong, 2013;Tavazzi et al, 2014], normal proliferation of CNS cells attempting to maintain homeostasis in the presence of a viral infection [Cassol et al, 2014;Vartak-Sharma et al, 2016], aquaporin dysregulation [Aoki-Yoshino et al, 2005;Benga and Huber, 2012;Xing et al, 2016], neurotropic factor dysregulation [Gage et al, 1989;Fields et al, 2014] and expansion of neuronal somas during infection prior to apoptosis [Kaul et al, 2001;Mbita et al, 2014]. It is possible that one or more of these cellular mechanisms drive the pattern of atrophy/hypertrophy found in this study and that the co-occurrence of these events is obscured when assessing the entire structure as a single volume.…”

Section: Discussionmentioning

confidence: 99%

The effects of HIV and aging on subcortical shape alterations: A 3D morphometric study

et al. 2016

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Standard volumetric neuroimaging studies have demonstrated preferential atrophy of subcortical structures among individuals with HIV. However, to our knowledge, no study has investigated subcortical shape alterations secondary to HIV and whether advancing age impacts that relationship. This study employed 3D morphometry to examine the independent and interactive effects of HIV and age on shape differences in nucleus accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus in 81 participants ranging in age from 24 – 76 including 59 HIV+ individuals and 22 HIV-seronegative controls. T1-weighted MRI underwent a pre-processing pipeline followed by automated subcortical segmentation. Parametric statistical analyses were used to determine independent effects of HIV infection and age on volume and shape in each region of interest (ROI) and the interaction between age and HIV serostatus in predicting volume/shape in each ROI. Significant main effects for HIV were found in the shape of right caudate and nucleus accumbens, left pallidum and hippocampus. Age was associated with differences in shape in left pallidum, right nucleus accumbens and putamen, and bilateral caudate, hippocampus and thalamus. Of greatest interest, an age*HIV interaction effect was found in the shape of bilateral nucleus accumbens, amygdala, caudate, and thalamus as well as right pallidum and putamen such that increasing age in HIV participants was associated with greater shape alterations. Traditional volumemetric analyses revealed main effects for both HIV and age but no age*HIV interaction. These findings may suggest that age and HIV infection conferred additional deleterious effects on subcortical shape abnormalities beyond the independent effects of these factors.

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“…The numbers of astrocytes do not change dramatically in the old compared to the young, at least in human (Rodriguez-Arellano et al, 2016; Vartak-Sharma et al, 2016). Yet, age-related alterations can still be detected in senile astrocytes.…”

Section: Impact Of Aging On the Components Of The Nvumentioning

confidence: 97%

Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect

Cai

Zhang

et al. 2017

Ageing Research Reviews

238

184

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Current understanding on the mechanisms of brain injury and neurodegeneration highlights an appreciation of multicellular interactions within the neurovascular unit (NVU), which include the evolution of blood-brain barrier (BBB) damage, neuronal cell death or degeneration, glial reaction, and immune cell infiltration. Aging is an important factor that influences the integrity of the NVU. The age-related physiological or pathological changes in the cellular components of the NVU have been shown to increase the vulnerability of the NVU to ischemia/reperfusion injury or neurodegeneration, and to result in deteriorated brain damage. This review describes the impacts of aging on each NVU component and discusses the mechanisms by which aging increases NVU sensitivity to stroke and neurodegenerative diseases. Prophylactic or therapeutic perspectives that may delay or diminish aging and thus prevent the incidence of these neurological disorders will also be reviewed.

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Astrocyte elevated gene-1 (AEG-1) and the A(E)Ging HIV/AIDS-HAND

Cited by 23 publications

References 313 publications

HIV-1-associated inflammation and antiretroviral therapy regulate astrocyte endoplasmic reticulum stress responses

HIV-1-associated inflammation and antiretroviral therapy regulate astrocyte endoplasmic reticulum stress responses

The effects of HIV and aging on subcortical shape alterations: A 3D morphometric study

Dysfunction of the neurovascular unit in ischemic stroke and neurodegenerative diseases: An aging effect

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