HIV and Alzheimer’s disease: complex interactions of HIV-Tat with amyloid β peptide and Tau protein

Hategan, Alina; Masliah, Eliezer; Nath, Avindra

doi:10.1007/s13365-019-00736-z

Cited by 34 publications

(31 citation statements)

References 118 publications

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“…Likewise, APP transcription was suppressed by Meth sensitization, by Tat expression, as well as by their interaction. Although a decrease in APP is regarded as protective, it could be a factor limiting β-APP supply [106][107][108]. Whether these are replicating human disease and showing signs of accelerated aging in this model, as a consequence of Meth and HIV Tat interaction, needs to be further examined.…”

Section: Discussionmentioning

confidence: 97%

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Basova

Kesby

Kaul

et al. 2020

Viruses

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Methamphetamine (Meth) abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein, trans-activator of transcription (Tat), has been described to induce changes in brain gene transcription that can result in impaired reward circuitry, as well as in inflammatory processes. In transgenic mice with doxycycline-induced Tat protein expression in the brain, i.e., a mouse model of neuroHIV, we tested global gene expression patterns induced by Meth sensitization. Meth-induced locomotor sensitization included repeated daily Meth or saline injections for seven days and Meth challenge after a seven-day abstinence period. Brain samples were collected 30 min after the Meth challenge. We investigated global gene expression changes in the caudate putamen, an area with relevance in behavior and HIV pathogenesis, and performed pathway and transcriptional factor usage predictions using systems biology strategies. We found that Tat expression alone had a very limited impact in gene transcription after the Meth challenge. In contrast, Meth-induced sensitization in the absence of Tat induced a global suppression of gene transcription. Interestingly, the interaction between Tat and Meth broadly prevented the Meth-induced global transcriptional suppression, by maintaining regulation pathways, and resulting in gene expression profiles that were more similar to the controls. Pathways associated with mitochondrial health, initiation of transcription and translation, as well as with epigenetic control, were heavily affected by Meth, and by its interaction with Tat in anti-directional ways. A series of systems strategies have predicted several components impacted by these interactions, including mitochondrial pathways, mTOR/RICTOR, AP-1 transcription factor, and eukaryotic initiation factors involved in transcription and translation. In spite of the antagonizing effects of Tat, a few genes identified in relevant gene networks remained downregulated, such as sirtuin 1, and the amyloid precursor protein (APP). In conclusion, Tat expression in the brain had a low acute transcriptional impact but strongly interacted with Meth sensitization, to modify effects in the global transcriptome.

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Section: Discussionmentioning

confidence: 97%

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Basova

Kesby

Kaul

et al. 2020

Viruses

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“…Previous studies indicate that HIV persists in an expressed state in the central nervous system of HIV-infected persons on effective antiretroviral therapy ( Heaton et al, 2011 ; Gelman et al, 2013 ), likely contributing to the observed chronic cognitive disease they suffer. There is currently no treatment for HIV–NCI and multiple observations show that the disease worsens with age ( Brouillette et al, 2016 ; Goodkin et al, 2017 ), overlapping and potentially synergizing with cognitive aging and age-related neurological diseases ( Hategan et al, 2017 , 2019 ).…”

Section: Discussionmentioning

confidence: 99%

Prevention and treatment of HIV infection and cognitive disease in mice by innate immune responses

Dong

Borjabad

Kelschenbach

et al. 2020

Brain, Behavior, & Immunity - Health

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HIV associated neurocognitive impairment afflicts roughly half of infected individuals on antiretroviral therapy. This disease currently has no treatment. We have previously shown that type I interferon is induced by and partially controls infection and neuropathogenesis in mice infected by chimeric HIV, EcoHIV. Here we investigate the intentional ligation of the pattern recognition receptor Toll-like receptor 3 (TLR3) by polyinosinic-polycytidylic acid (poly I:C) for its ability to prevent or control infection and associated cognitive disease in EcoHIV infected mice. We tested topical, injection, and intranasal application of poly I:C in mice during primary infection through injection or sexual transmission or in established infection. We measured different forms of HIV DNA and RNA in tissues by real-time PCR and the development of HIV-associated cognitive disease by the radial arm water maze behavioral test. Our results indicate that poly I:C blocks primary EcoHIV infection of mice prior to reverse transcription and reduces established EcoHIV infection. Prevention or control of viral replication by poly I:C prevents or reverses HIV associated cognitive disease in mice. These findings indicate that poly I:C or other innate immune agonists may be useful in control of HIV cognitive disease.

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“…For example, progressive accumulation of aberrant proteins such as pTau, Aβ and α-synuclein are accompanied by damage to selective neural circuits, neuroinflammation, gliosis and vascular alterations are common in both HIV and AD (Mackiewicz et al, 2019 ). In fact, the HIV protein Tat that may be released from infected astrocytes, even during effective anti-retroviral therapy, is believed to be a major factor in promoting pTau and Aβ formation and accumulation (Hategan et al, 2019 ). Taken together, even though limited, current evidence indicates that changes in AQP4 localization on astrocytes and decreased waste clearance may involve increased A2aR activity.…”

Section: Aqp4 Dysregulation Adenosine A2a Receptor and Neurodegeneramentioning

confidence: 99%

Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

Tice¹,

McDevitt

Langford³

2020

Front. Cell. Infect. Microbiol.

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The discovery of the glial-lymphatic or glymphatic fluid clearance pathway in the rodent brain led researchers to search for a parallel system in humans and to question the implications of this pathway in neurodegenerative diseases. Magnetic resonance imaging studies revealed that several features of the glymphatic system may be present in humans. In both rodents and humans, this pathway promotes the exchange of interstitial fluid (ISF) and cerebrospinal fluid (CSF) through the arterial perivascular spaces into the brain parenchyma. This process is facilitated in part by aquaporin-4 (AQP4) water channels located primarily on astrocytic end feet that abut cerebral endothelial cells of the blood brain barrier. Decreased expression or mislocalization of AQP4 from astrocytic end feet results in decreased interstitial flow, thereby, promoting accumulation of extracellular waste products like hyperphosphorylated Tau (pTau). Accumulation of pTau is a neuropathological hallmark in Alzheimer's disease (AD) and is accompanied by mislocalization of APQ4 from astrocyte end feet to the cell body. HIV infection shares many neuropathological characteristics with AD. Similar to AD, HIV infection of the CNS contributes to abnormal aging with altered AQP4 localization, accumulation of pTau and chronic neuroinflammation. Up to 30% of people with HIV (PWH) suffer from HIV-associated neurocognitive disorders (HAND), and changes in AQP4 may be clinically important as a contributor to cognitive disturbances. In this review, we provide an overview and discussion of the potential contributions of NeuroHIV to glymphatic system functions by focusing on astrocytes and AQP4. Although HAND encompasses a wide range of neurocognitive impairments and levels of neuroinflammation vary among and within PWH, the potential contribution of disruption in AQP4 may be clinically important in some cases. In this review we discuss implications for possible AQP4 disruption on NeuroHIV disease trajectory and how HIV may influence AQP4 function.

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HIV and Alzheimer’s disease: complex interactions of HIV-Tat with amyloid β peptide and Tau protein

Cited by 34 publications

References 118 publications

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Systems Biology Analysis of the Antagonizing Effects of HIV-1 Tat Expression in the Brain over Transcriptional Changes Caused by Methamphetamine Sensitization

Prevention and treatment of HIV infection and cognitive disease in mice by innate immune responses

Astrocytes, HIV and the Glymphatic System: A Disease of Disrupted Waste Management?

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