RESUMO
We examined whether cognitive reserve moderated the relationship between neurodegeneration and cognition in 67 postmortem persons with HIV (PWH) who were cognitively assessed within 1 year of death. Cognitive reserve was measured via the Wide Range Achievement Test-4 reading subtest (WRAT4). Synaptodendritic neurodegeneration was based on densities of synaptophysin and microtubule-associated protein 2 immunohistochemical reactivity in frontal cortex, and categorized as minimal, moderate, or severe (tertile-split). T-Scores from 15 cognitive tests were averaged into a global cognitive T-score. Among those with low cognitive reserve (based on WRAT4 median split), the moderate neurodegeneration group showed cognition that was poorer than the minimal neurodegeneration group and comparable to the severe neurodegeneration group. Among those with high cognitive reserve, the moderate neurodegeneration group showed cognition comparable to the minimal neurodegeneration group and better than the severe neurodegeneration group. High cognitive reserve may buffer against cognitive impairment among PWH with moderate, but not severe, neurodegeneration.
Assuntos
Disfunção Cognitiva , Reserva Cognitiva , Infecções por HIV , Humanos , Infecções por HIV/patologia , Disfunção Cognitiva/complicações , Cognição , Testes NeuropsicológicosRESUMO
Given the co-occurrence of memory impairment in HIV-associated neurocognitive disorders (HAND) and amnestic mild cognitive impairment/Alzheimer's disease (aMCI/AD), biomarkers are needed that can disentangle these conditions among people with HIV (PWH). We assessed whether cerebrospinal fluid (CSF) markers of AD could help in this effort by determining their relationship to learning and memory deficits versus cognitive deficits more characteristic of HAND than aMCI/AD (processing speed and complex visual/motor coordination) among 31 older PWH. CSF amyloid-ß42 phosphorylated-tau, amyloid-ß40/amyloid-ß42 and phosphorylated-tau/amyloid-ß42 ratio related to learning/memory performance but not HAND-related deficits, suggesting that these biomarkers may have utility in disentangling aMCI/AD from HAND.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Infecções por HIV , Idoso , Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Disfunção Cognitiva/psicologia , Infecções por HIV/complicações , Humanos , Transtornos da Memória , Testes Neuropsicológicos , Fragmentos de Peptídeos/líquido cefalorraquidiano , Projetos Piloto , Proteínas tau/líquido cefalorraquidianoRESUMO
BACKGROUND: Memory impairment occurs in human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) and amnestic mild cognitive impairment (aMCI), the precursor to Alzheimer disease (AD). Methods are needed to distinguish aMCI-associated from HAND-associated impairment in people with HIV (PWH). We developed a neuropsychological method of identifying aMCI in PWH and tested this by relating AD neuropathology (ß-amyloid, phospho-Tau) to aMCI versus HAND classification. METHODS: Seventy-four HIV-positive cases (aged 50-68 years) from the National NeuroAIDS Tissue Consortium had neurocognitive data within 1 year of death and data on ß-amyloid and phospho-Tau pathology in frontal brain tissue. High aMCI risk was defined as impairment (<1.0 SD below normative mean) on 2 of 4 delayed recall or recognition outcomes from a verbal and nonverbal memory test (at least 1 recognition impairment required). Differences in ß-amyloid and phospho-Tau by aMCI and HAND classification were examined. RESULTS: High aMCI risk was more common in HAND (69.0%) versus no HAND (37.5%) group. ß-amyloid pathology was 4.75 times more likely in high versus low aMCI risk group. Phospho-Tau pathology did not differ between aMCI groups. Neither neuropathological feature differed by HAND status. CONCLUSIONS: Amnestic mild cognitive impairment criteria that include recognition impairment may help to detect AD-like cognitive/biomarker profiles among PWH.
Assuntos
Disfunção Cognitiva , Infecções por HIV , Doença de Alzheimer/diagnóstico , Peptídeos beta-Amiloides , Disfunção Cognitiva/diagnóstico , Disfunção Cognitiva/etiologia , Infecções por HIV/complicações , Humanos , Testes NeuropsicológicosRESUMO
Due to a production error data in Table 1 were not presented correctly.
RESUMO
HIV-associated neurocognitive disorders (HAND) describe a spectrum of neuropsychological impairment caused by HIV-1 infection. While the sequence of cellular and physiological events that lead to HAND remains obscure, it likely involves chronic neuroinflammation. Host genetic markers that increase the risk for HAND have been reported, but replication of such studies is lacking, possibly due to inconsistent application of a behavioral phenotype across studies. In the current study, we used histopathologic phenotypes in order to validate putative risk alleles for HAND. The National NeuroAIDS Tissue Consortium, a longitudinal study of the neurologic manifestations of HIV. Data and specimens were obtained from 175 HIV-infected adults. After determining several potential covariates of neurocognitive functioning, we quantified levels of six histopathological markers in the frontal lobe in association with neurocognitive functioning: SYP, MAP 2, HLA-DR, Iba1, GFAP, and ß-amyloid. We then determined alleles of 15 candidate genes for their associations with neurocognitive functioning and histopathological markers. Finally, we identified the most plausible causal pathway based on our data using a multi-stage linear regression-based mediation analysis approach. None of the genetic markers were associated with neurocognitive functioning. Of the histopathological markers, only MAP 2 and SYP were associated with neurocognitive functioning; however, MAP 2 and SYP did not vary as a function of genotype. Mediation analysis suggests a causal pathway in which presynaptic degeneration (SYP) leads to somatodendritic degeneration (MAP 2) and ultimately neurocognitive impairment. This study did not support the role of host genotype in the histopathology underlying HAND. The findings lend further support for synaptodendritic degeneration as the proximal underlying neuropathological substrate of HAND.
Assuntos
Disfunção Cognitiva/genética , Dendritos/patologia , Infecções por HIV/genética , Proteínas Associadas aos Microtúbulos/genética , Sinapses/patologia , Sinaptofisina/genética , Adulto , Disfunção Cognitiva/complicações , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/patologia , Citocinas/genética , Dendritos/genética , Dendritos/metabolismo , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Expressão Gênica , Genótipo , Infecções por HIV/complicações , Infecções por HIV/metabolismo , Infecções por HIV/patologia , Humanos , Estudos Longitudinais , Masculino , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Testes Neuropsicológicos , Fenótipo , Polimorfismo Genético , Terminações Pré-Sinápticas/metabolismo , Terminações Pré-Sinápticas/patologia , Sinapses/genética , Sinapses/metabolismo , Sinaptofisina/metabolismoRESUMO
The handling-induced dark neuron is a histological artifact observed in brain samples handled before fixation with aldehydes. To explore associations between dark neurons and immunohistochemical alterations in mouse brains, we examined protein products encoded by Cav3 (neuronal perikarya/neurites), Rbbp4 (neuronal nuclei), Gfap (astroglia), and Aif1 (microglia) genes in adjacent tissue sections. Here, dark neurons were incidental findings from our prior project, studying the effects of age and high-fat diet on metabolic homeostasis in male C57BL/6N mice. Available were brains from 4 study groups: middle-aged/control diet, middle-aged/high-fat diet, old/control diet, and old/high-fat diet. Young/control diet mice were used as baseline. The hemibrains were immersion-fixed with paraformaldehyde and paraffin-embedded. In the hippocampal formation, we found negative correlations between dark neuron hyperbasophilia and immunoreactivity for CAV3, RBBP4, and glial fibrillary acidic protein (GFAP) using quantitative image analysis. There was no significant difference in dark neuron hyperbasophilia or immunoreactivity for any protein examined among all groups. In contrast, in the hippocampal fimbria, old age seemed to be associated with higher immunoreactivity for GFAP and allograft inflammatory factor-1. Our findings suggest that loss of immunohistochemical reactivity for CAV3, RBBP4, and GFAP in the hippocampal formation is an artifact associated with the occurrence of dark neurons. The unawareness of dark neurons may lead to misinterpretation of immunohistochemical reactivity alterations.
Assuntos
Artefatos , Biomarcadores/análise , Imuno-Histoquímica , Neurônios , Manejo de Espécimes/efeitos adversos , Animais , Hipocampo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/metabolismoRESUMO
With increasing age, the general population is increasingly vulnerable to the development of cerebral amyloid-ß (Aß) plaque and neuronal phospho-tau (p-tau) pathology. In HIV disease, prior studies of these neuropathologic changes were relatively limited. Here, we characterized Aß plaques and p-tau lesions by immunohistochemistry in relevant brain regions (prefrontal neocortex, putamen, basal-temporal neocortex, and hippocampus) of HIV-infected adults. We used multivariable logistic regression to predict regional Aß plaque or p-tau pathology based on demographic factors, apolipoprotein E (APOE) genotypes, HIV disease-related factors, and regional gliosis. We used multiple linear regression to predict T-scores in neuropsychological domains based on regional Aß plaque or p-tau pathology. We found that APOE ε4 alleles, older age, and higher plasma HIV-1 RNA predicted prefrontal Aß plaques (odds ratio (OR) 5.306, 1.045, and 0.699, respectively, n = 168). Older age predicted putamen Aß plaques (OR 1.064, n = 171). APOE ε4 alleles, hepatitis C virus seropositivity, and higher plasma HIV-1 RNA predicted hippocampus Aß plaques (OR 6.779, 6.138, and 0.589, respectively, n = 56). The p-tau lesions were sparse in the vast majority of affected cases. Lifetime substance use disorder and higher plasma HIV-1 RNA predicted putamen p-tau lesions (OR 0.278 and 0.638, respectively, n = 67). Older age and gliosis predicted hippocampus p-tau lesions (OR 1.128 and 0.592, respectively, n = 59). Prefrontal Aß plaques predicted lower speed of information processing (n = 159) and putamen Aß plaques predicted lower levels of attention and working memory (n = 88). Regional p-tau lesions were not significantly predictive of any neuropsychological domains. In conclusion, Aß plaque or p-tau pathology in different brain regions was predicted by different sets of biological factors. Aß plaques in prefrontal neocortex and putamen predicted poorer functioning in cognitive domains relevant to these brain regions. The absence of significant impact of regional p-tau lesions on neuropsychological functioning might be explained by the subthreshold burden of p-tau lesions.
Assuntos
Encéfalo/patologia , Cognição , Infecções por HIV/patologia , Emaranhados Neurofibrilares/patologia , Placa Amiloide/patologia , Adulto , Idoso , Peptídeos beta-Amiloides/metabolismo , Feminino , Infecções por HIV/complicações , HIV-1 , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Proteínas tau/metabolismoRESUMO
Methamphetamine (Meth) use is common among HIV-infected persons. It remains unclear whether Meth dependence is associated with long-lasting degenerative changes in the brain parenchyma and microvasculature of HIV-infected individuals. We examined the postmortem brains of 78 HIV-infected adults, twenty of whom were diagnosed with lifetime Meth dependence (18 past and two current at the final follow-up visit). Using logistic regression models, we analyzed associations of Meth with cerebral gliosis (immunohistochemistry for ionized calcium-binding adapter molecule-1 (Iba1) and glial fibrillary acidic protein (GFAP) in frontal, temporo-parietal, and putamen-internal capsule regions), synaptodendritic loss (confocal microscopy for synaptophysin (SYP) and microtubule-associated protein-2 (MAP2) in frontal cortex), ß-amyloid plaque deposition (immunohistochemistry in frontal and temporo-parietal cortex and putamen), and arteriolosclerosis (histopathology in forebrain white matter). We found that Meth was associated with marked Iba1 gliosis in the temporo-parietal region (odds ratio, 4.42 (95 % confidence interval, 1.36, 14.39), p = 0.014, n = 62), which remained statistically significant after adjusting for HIV encephalitis, white matter lesions, and opportunistic diseases (n = 61); hepatitis C virus seropositivity (n = 54); and lifetime dependence on alcohol, opiates, and cannabis (n = 62). There was no significant association of Meth with GFAP gliosis, SYP or MAP2 loss, ß-amyloid plaque deposition, or arteriolosclerosis. In conclusion, we found lifetime Meth dependence to be associated with focal cerebral microgliosis among HIV-infected adults, but not with other brain degenerative changes examined. Some of the changes in select brain regions might be reversible following extended Meth abstinence or, alternatively, might have not been induced by Meth initially.
Assuntos
Alcoolismo/fisiopatologia , Transtornos Relacionados ao Uso de Anfetaminas/fisiopatologia , Gliose/fisiopatologia , Infecções por HIV/fisiopatologia , Transtornos Relacionados ao Uso de Opioides/fisiopatologia , Adulto , Idoso , Alcoolismo/complicações , Alcoolismo/genética , Alcoolismo/patologia , Transtornos Relacionados ao Uso de Anfetaminas/complicações , Transtornos Relacionados ao Uso de Anfetaminas/genética , Transtornos Relacionados ao Uso de Anfetaminas/patologia , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/metabolismo , Autopsia , Proteínas de Ligação ao Cálcio , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Feminino , Lobo Frontal/metabolismo , Lobo Frontal/patologia , Lobo Frontal/fisiopatologia , Expressão Gênica , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Gliose/complicações , Gliose/genética , Gliose/patologia , Infecções por HIV/complicações , Infecções por HIV/genética , Infecções por HIV/patologia , Humanos , Masculino , Proteínas dos Microfilamentos , Proteínas Associadas aos Microtúbulos/genética , Proteínas Associadas aos Microtúbulos/metabolismo , Pessoa de Meia-Idade , Transtornos Relacionados ao Uso de Opioides/complicações , Transtornos Relacionados ao Uso de Opioides/genética , Transtornos Relacionados ao Uso de Opioides/patologia , Lobo Parietal/metabolismo , Lobo Parietal/patologia , Lobo Parietal/fisiopatologia , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Prosencéfalo/fisiopatologia , Putamen/metabolismo , Putamen/patologia , Putamen/fisiopatologia , Sinaptofisina/genética , Sinaptofisina/metabolismo , Lobo Temporal/metabolismo , Lobo Temporal/patologia , Lobo Temporal/fisiopatologiaRESUMO
The neuropathogenesis of HIV-associated neurocognitive disorders (HAND) remains puzzling. We interrogated several levels of data (host genetic, histopathology, brain viral load, and neurocognitive) to identify histopathological changes most relevant to HAND. The design of the study is a clinicopathological study employing genetic association analyses. Data and brain tissue from 80 HIV-infected adults were used. Markers in monocyte chemoattractant protein-1 (MCP-1), interleukin 1-alpha (IL1-α), macrophage inflammatory protein 1-alpha (MIP1-α), DRD3, DRD2, and apolipoprotein E (ApoE) were genotyped. Microtubule associated protein 2 (MAP2), synaptophysin (SYP), human leukocyte antigen-DR (HLA-DR), glial fibrillary acidic protein (GFAP), amyloid beta (A-Beta), and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactivity were quantified in the frontal cortex, putamen, and hippocampus. A composite score for each marker (mean of the three brain regions) was used. Neurocognitive functioning and other clinical variables were determined within 1 year of death. Brain HIV RNA viral load was available for a subset of cases. MAP2 and SYP proved most relevant to neurocognitive functioning. Immunoreactivity of these markers, as well as A-Beta and Iba-1, was correlated with brain HIV RNA viral load. Several genetic markers in combination with other factors predicted histopathology: HIV blood viral load, MIP1-α genotype, and DRD3 genotype predicted Iba-1 immunoreactivity; the duration of infection and IL1-α genotype predicted GFAP immunoreactivity; ApoE genotype and age at death predicted A-Beta immunoreactivity. These data indicate that HIV replication in the brain is the primary driving force leading to neuroinflammation and dysfunctional protein clearance, as reflected by A-Beta and Iba-1. Downstream to these changes are synaptodendritic degeneration, which is the immediate histopathological substrate of the neurocognitive impairment characteristic of HAND. These intermediate histopathological phenotypes are influenced by host genetic polymorphisms in genes encoding cytokines/chemokines, neuronal protein clearance pathways, and dopaminergic factors.
Assuntos
Complexo AIDS Demência/patologia , Proteínas Associadas aos Microtúbulos/genética , Análise Multinível , Sinaptofisina/genética , Replicação Viral , Complexo AIDS Demência/genética , Complexo AIDS Demência/imunologia , Complexo AIDS Demência/virologia , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Adulto , Peptídeos beta-Amiloides/genética , Peptídeos beta-Amiloides/imunologia , Biomarcadores/metabolismo , Proteínas de Ligação ao Cálcio , Quimiocina CCL2/genética , Quimiocina CCL2/imunologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Feminino , Lobo Frontal/imunologia , Lobo Frontal/patologia , Lobo Frontal/virologia , Expressão Gênica , Hipocampo/imunologia , Hipocampo/patologia , Hipocampo/virologia , Humanos , Interleucina-1alfa/genética , Interleucina-1alfa/imunologia , Masculino , Proteínas dos Microfilamentos , Proteínas Associadas aos Microtúbulos/imunologia , Pessoa de Meia-Idade , Putamen/imunologia , Putamen/patologia , Putamen/virologia , Receptores Dopaminérgicos/genética , Receptores Dopaminérgicos/imunologia , Índice de Gravidade de Doença , Sinaptofisina/imunologia , Carga ViralRESUMO
HIV infection leads to age-related conditions in relatively young persons. HIV-associated neurocognitive disorders (HAND) are considered among the most prevalent of these conditions. To study the mechanisms underlying this disorder, researchers need an accurate method for measuring biological aging. Here, we apply a recently developed measure of biological aging, based on DNA methylation, to the study of biological aging in HIV+ brains. Retrospective analysis of tissue bank specimens and pre-mortem data was carried out. Fifty-eight HIV+ adults underwent a medical and neurocognitive evaluation within 1 year of death. DNA was obtained from occipital cortex and analyzed with the Illumina Infinium Human Methylation 450K platform. Biological age determined via the epigenetic clock was contrasted with chronological age to obtain a measure of age acceleration, which was then compared between those with HAND and neurocognitively normal individuals. The HAND and neurocognitively normal groups did not differ with regard to demographic, histologic, neuropathologic, or virologic variables. HAND was associated with accelerated aging relative to neurocognitively normal individuals, with average relative acceleration of 3.5 years. Age acceleration did not correlate with pre-mortem neurocognitive functioning or HAND severity. This is the first study to demonstrate that the epigenetic age of occipital cortex samples is associated with HAND status in HIV+ individuals pre-mortem. While these results suggest that the increased risk of a neurocognitive disorder due to HIV might be mediated by an epigenetic aging mechanism, future studies will be needed to validate the findings and dissect causal relationships and downstream effects.
Assuntos
Aceleração , Envelhecimento/genética , Disfunção Cognitiva/genética , Epigênese Genética , Infecções por HIV/genética , Lobo Occipital/metabolismo , Adulto , Envelhecimento/patologia , Autopsia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/virologia , Metilação de DNA , Feminino , Infecções por HIV/complicações , Infecções por HIV/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Lobo Occipital/virologia , Estudos RetrospectivosRESUMO
Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aß42. Additionally, a larger cohort of 250 autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.
Assuntos
Doença de Alzheimer , Amiloidose , Infecções por HIV , Idoso , Humanos , Pessoa de Meia-Idade , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Peptídeos beta-Amiloides/metabolismo , Encéfalo/patologia , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagem , Estudos de Coortes , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Estudos Prospectivos , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismoRESUMO
Reverse transcriptase inhibitors (RTIs) are currently broadly prescribed for the treatment of HIV infection but are also thought to prevent Alzheimer's Disease (AD) progression by protecting against amyloidosis. Our study evaluates the hypothesis that reverse transcriptase inhibitors protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection. We compiled a case series of participants from a prospective study of the neurological consequences of HIV infection at the HIV Neurobehavioral Research Program (HNRP) who had serial neuropsychological and neurological assessments and were on RTIs. Two participants had gross and microscopic examination and immunohistochemistry of the brain at autopsy; one was assessed clinically for Alzheimer's Disease by cerebrospinal fluid (CSF) analysis of phosphorylated-Tau, Total-Tau and Aß42. Additionally, a larger cohort of autopsied individuals was evaluated for presence of amyloid plaques, Tau, and related pathologies. Three older, virally suppressed individuals with HIV who had long-term treatment with RTIs were included in analyses. Two cases demonstrated substantial cerebral amyloid deposition at autopsy. The third case met clinical criteria for AD based on a typical clinical course and CSF biomarker profile. In the larger cohort of autopsied individuals, the prevalence of cerebral amyloidosis among people with HIV (PWH) was greater for those on RTIs. Our study showed that long-term RTI therapy did not protect against Alzheimer-type brain amyloidogenesis in the context of HIV infection in these patients. Given the known toxicities of RTIs, it is premature to recommend them to individuals at risk or with Alzheimer's disease who do not have HIV infection.
RESUMO
BACKGROUND: Airway remodeling is associated with severity and treatment insensitivity in asthma. This study aimed to investigate the effects of G protein-coupled receptor 120 (GPR120) stimulation on alleviating allergic inflammation and remodeling of airway epithelium. RESEARCH DESIGN AND METHODS: Ovalbumin (OVA)-challenged BALB/c mice and type-2-cytokine (IL-4 and IL-13)-exposed 16HBE human bronchial epithelial cells were treated with GSK137647A, a selective GPR120 agonist. Markers of allergic inflammation and airway remodeling were determined. RESULTS: GSK137647A attenuated inflammation and mucus secretion in airway epithelium of OVA-challenged mice. Stimulation of GPR120 in 16HBE suppressed expression of asthma-associated cytokines and cytokine-induced expression of pathogenic mucin-MUC5AC. These effects were abolished by co-treatment with AH7614, a GPR120 antagonist. Moreover, GPR120 stimulation in 16HBE cells reduced expression of fibrotic markers including fibronectin protein and ACTA2 mRNA and inhibited epithelial barrier leakage induced by type-2 inflammation via rescuing expression of zonula occludens-1 protein. Furthermore, GPR120 stimulation prevented the cytokine-induced airway epithelial remodeling via suppression of STAT6 and Akt phosphorylation. CONCLUSIONS: Our findings suggest that GPR120 activation alleviates allergic inflammation and remodeling of airway epithelium partly through inhibition of STAT6 and Akt. GPR120 may represent a novel therapeutic target for diseases associated with remodeling of airway epithelium, including asthma.
Assuntos
Asma , Interleucina-13 , Humanos , Animais , Camundongos , Interleucina-13/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interleucina-4/farmacologia , Interleucina-4/metabolismo , Remodelação das Vias Aéreas , Transdução de Sinais , Modelos Animais de Doenças , Asma/metabolismo , Citocinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Inflamação/metabolismo , Ovalbumina/farmacologia , Camundongos Endogâmicos BALB C , Pulmão/patologia , Fator de Transcrição STAT6/metabolismoRESUMO
Neurocognitive deficits are prevalent among people living with HIV, likely due to chronic inflammation and oxidative stress in the brain. To date, no pharmaceutical treatments beyond antiretroviral therapy (ARV) has been shown to reduce risk for, or severity of, HIV-associated neurocognitive disorder. Here we investigate a novel compound, CDDO-Me, with documented neuroprotective effects via activation of the nrf2 and inhibition of the NFkB pathways. Methods: We conducted three studies to assess the efficacy of CDDO-Me alone or in combination with antiretroviral therapy in humanized mice infected with HIV; behavioral, histopathological, and immunohistochemical. Results: CDDO-Me in combination with ARV rescued social interaction deficits; however, only ARV was associated with preserved functioning in other behaviors, and CDDO-Me may have attenuated those benefits. A modest neuroprotective effect was found for CDDO-Me when administered with ARV, via preservation of PSD-95 expression; however, ARV alone had a more consistent protective effect. No significant changes in antioxidant enzyme expression levels were observed in CDDO-Me-treated animals. Only ARV use seemed to affect some antioxidant levels, indicating that it is ARV rather than CDDO-Me that is the major factor providing neuroprotection in this animal model. Finally, immunohistochemical analysis found that several cellular markers in various brain regions varied due to ARV rather than CDDO-Me. Conclusion: Limited benefit of CDDO-Me on behavior and neuroprotection were observed. Instead, ARV was shown to be the more beneficial treatment. These experiments support the future use of this chimeric mouse for behavioral experiments in neuroHIV research.
RESUMO
We determined the prevalence of Alzheimer's disease (AD) pathological hallmarks, amyloid-ß and phosphorylated-Tau, in autopsied brains of 49 people with HIV (PWH) (ages: 50-68; mean age = 57.0) from the National NeuroAIDS Tissue Consortium and in a comparative cohort of 55 people without HIV (PWoH) from the UC San Diego Alzheimer's Disease Research Center (17 controls, 14 mild cognitive impairment, 24 AD; ages: 70-102, mean age = 88.7). We examined how AD pathology relates to domain-specific cognitive functions in PWH overall and in sex-stratified samples. Amyloid-ß and phosphorylated-Tau positivity (presence of pathology of any type/density) was determined via immunohistochemistry in AD-sensitive brain regions. Among PWH, amyloid-ß positivity ranged from 19% (hippocampus) to 41% (frontal neocortex), and phosphorylated-Tau positivity ranged from 47% (entorhinal cortex) to 73% (transentorhinal cortex). Generally, AD pathology was significantly less prevalent, and less severe when present, in PWH versus PWoH regardless of cognitive status. Among PWH, positivity for AD pathology related most consistently to memory-related domains. Positivity for p-Tau pathology related to memory-related domains in women with HIV only, although the sample size of women with HIV was small (n = 10). Results indicate that AD pathology is present in a sizable portion of middle aged and older PWH, although not to the extent in older PWoH. Studies with better age-matched PWoH are needed to examine the effect of HIV status on AD pathology.
Assuntos
Doença de Alzheimer , Envelhecimento Saudável , Humanos , Pessoa de Meia-Idade , Feminino , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/patologia , Proteínas tau , Cognição , Peptídeos beta-Amiloides , BiomarcadoresRESUMO
FK506 binding protein (FKBP)-51 and FKBP52 act as molecular chaperones to control glucocorticoid receptor (GR) sensitivity. Dysregulation of proteins involved in GR-mediated signaling can lead to maladaptive stress response and aging-related cognitive decline. As HIV infection is related to chronic stress, we hypothesized that altered cortical expression of these proteins was associated with HIV-associated neurocognitive disorders (HAND). We used quantitative immunohistochemistry to assess expression levels of these proteins in the mid-frontal gyrus of 55 HIV-infected subjects free of cerebral opportunistic diseases compared to 20 age-matched non-HIV controls. The immunoreactivity normalized to the neuroanatomic area measured (IRn) for FKBP51 was increased in HIV subjects both in the cortex and subcortical white matter (p < 0.0001, U test), while no significant alterations were observed for GR or FKBP52. Notably, the cortical FKBP51 IRn was higher in HAND subjects than in cognitively normal HIV subjects (p = 0.02, U test). There was also a trend for increasing cortical FKBP51 IRn with the increasing severity of HAND (p = 0.08, Kruskal-Wallis test). No significant changes in FKBP51 IRn were found with respect to hepatitis C virus infection, lifetime methamphetamine use, or antiretroviral treatment in HIV subjects. In conclusion, the increased cortical expression of FKBP51 (an inhibitor for GR activity) might represent negative feedback in an attempt to reduce GR sensitivity in the setting of chronic stress-induced elevation of GR-mediated signaling inherent in HIV infection. The further increased FKBP51 expression might lead to maladaptive stress response and HAND.
Assuntos
Complexo AIDS Demência/genética , Giro Para-Hipocampal/metabolismo , Proteínas de Ligação a Tacrolimo/genética , Complexo AIDS Demência/complicações , Complexo AIDS Demência/tratamento farmacológico , Complexo AIDS Demência/metabolismo , Adulto , Antirretrovirais/administração & dosagem , Antirretrovirais/uso terapêutico , Estudos de Casos e Controles , Feminino , Expressão Gênica , Hepacivirus/fisiologia , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/genética , Hepatite C Crônica/metabolismo , Humanos , Imuno-Histoquímica , Masculino , Metanfetamina/administração & dosagem , Metanfetamina/efeitos adversos , Pessoa de Meia-Idade , Giro Para-Hipocampal/patologia , Giro Para-Hipocampal/virologia , Transdução de Sinais/genética , Estresse Fisiológico/genética , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/genética , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Proteínas de Ligação a Tacrolimo/metabolismoRESUMO
Colistin is a last-resort polypeptide antibiotic widely used to treat against multidrug-resistant Gram-negative bacterial infections. However, this treatment is associated with nephrotoxicity. The aim of this study was to examine the potential protective effect of panduratin A, a bioactive compound of Boesenbergia rotunda, on colistin-induced nephrotoxicity in both in vivo and in vitro models. Intraperitoneal injection of 15 mg/kg colistin for 7 days markedly promoted renal tubular degeneration, increased blood urea nitrogen (BUN) levels, and upregulated the expression of renal injury biomarker and apoptosis proteins. In addition, treatment with colistin increased oxidative stress and apoptosis in mice kidney tissues. Interestingly, these defects were attenuated when co-administered of colistin with panduratin A (2.5 or 25 mg/kg). The underlying mechanisms of panduratin A attenuating colistin toxicity was investigated in human renal proximal tubular cells (RPTEC/TERT1). The mechanisms by which colistin-triggered cytotoxicity was determined by analysis of cell death, reactive oxygen species (ROS) levels, mitochondria function as well as the expression of proteins related to apoptosis pathway. Colistin treatment (200 µg/ml) significantly increased cell apoptosis, elevated ROS production, reduced mitochondrial membrane potential, and decreased anti-apoptotic protein (Bcl-2) expression. These effects were notably suppressed by co-treatment with panduratin A (5 µM). Collectively, panduratin A exerts as a novel nephroprotective agent to protect against colistin-induced renal injury by attenuating mitochondrial damage and renal cell apoptosis.
Assuntos
Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Colistina/efeitos adversos , Nefropatias/tratamento farmacológico , Mitocôndrias/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Animais , Antibacterianos/efeitos adversos , Linhagem Celular , Colistina/farmacologia , Células Epiteliais/efeitos dos fármacos , Humanos , Rim/efeitos dos fármacos , Rim/lesões , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Zingiberaceae/químicaRESUMO
Introduction In the current context of early diagnosis of HIV infection, immediate initiation of antiretroviral (ARV) therapy, and lifelong chronic treatment, the potential ARV toxicity is of particular concern. Emtricitabine (FTC) and tenofovir (TFV) are commonly used as backbone drugs in ARV regimens recommended for initial therapy of HIV infection. Here we assessed the effects of FTC and TFV exposure on senescence-associated ß-galactosidase (SA-ß-Gal) activity, a marker of cellular senescence, in human brain vascular cells. Design Multi-layer three-dimensional cell co-cultures and in vitro assays. Methods To mimic the small vessel wall structure in vivo, three types of primary human brain vascular cells (endothelial cells, smooth muscle cells, and pericytes) were co-cultured on three Alvetex Scaffold disks placed on top of each other in order (three-layer three-dimensional cell co-cultures) and exposed to clinically relevant concentrations of ARV drugs (FTC, TFV, or FTC+TFV combination) or vehicle for eight days (four or five biological replicates per condition, 18 replicates totally). The SA-ß-Gal activity was quantitatively assayed in vitro by using the chemiluminescent Galacto-Star System (T1012; Applied Biosystems, Thermo Fisher Scientific, Waltham, MA) in 54 protein lysates extracted from individual cell-culture disks. Three-factor analysis of variance (cell type, FTC, TFV) was used to assess differences in the SA-ß-Gal activity levels normalized by the corresponding total protein concentrations. Results There was a trend for the FTC by TFV interaction effect on SA-ß-Gal activity (P = 0.058). The effects of FTC and TFV were not significantly different among the three cell types. The overall effect of FTC was not significant when controlling for TFV and cell type. The overall effect of TFV was significant when controlling for FTC and cell type (F(1,48) = 30.61, P < 0.001, partial η2 = 0.389). In the absence of FTC, TFV raised SA-ß-Gal activity by 0.631 units on average, regardless of cell type (P < 0.001, partial η2 = 0.368). In the presence of FTC, TFV raised SA-ß-Gal activity by 0.303 units on average, regardless of cell type (P = 0.015, partial η2 = 0.118). Conclusion Our preliminary findings suggest that primary human brain vascular cells exposed to TFV at clinically relevant concentrations undergo cellular senescence. This potential adverse effect of TFV should be further studied in animal models of HIV infection.
RESUMO
OBJECTIVE: Determine concentrations of antiretroviral therapy (ART) drugs in the human brain. DESIGN: Cohort study of persons with HIV who consented to antemortem assessment and postmortem autopsy. METHODS: Eleven persons with HIV who were taking ART at the time of death and had detectable concentrations of at least one ART drug in intracardiac aspirate at autopsy were evaluated. Autopsies were performed within 24âh of death and brain tissue was stored at -80â°C. Concentrations of 11 ART drugs were measured in three brain regions (globus pallidus, cortical gray matter, white matter) by HPLC tandem mass spectrometry with a lower limit of quantification of 25âng/ml. RESULTS: Participants were mostly men (82%) with a mean age of 40.4 years. Drug concentrations in brain tissue were highly variable and exceeded published concentrations in cerebrospinal fluid for several drugs, including for tenofovir, efavirenz, and lopinavir. Drug concentrations correlated most strongly between cortical gray matter and globus pallidus (rhoâ=â0.70) but less well between globus pallidus and white matter (rhoâ=â0.43). Combining all drugs and brain regions (nâ=â89), higher drug concentrations in brain were associated with longer estimated duration of HIV infection (Pâ=â0.015), lower HIV RNA in plasma (Pâ=â0.0001), lower nadir CD4 T-cell count (Pâ=â0.053), and worse neurocognitive performance (Pâ=â0.017). CONCLUSION: This is the first analysis of ART drug concentrations in human brain tissue. Concentrations of several drugs in this analysis were similar to published concentrations in cerebrospinal fluid but others exceeded published concentrations. The association between higher drug concentrations in the brain and worse neurocognitive performance may indicate ART neurotoxicity.
Assuntos
Fármacos Anti-HIV/farmacocinética , Encéfalo/metabolismo , Infecções por HIV/tratamento farmacológico , Adulto , Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade , Contagem de Linfócito CD4 , Estudos de Coortes , Humanos , Masculino , Carga ViralRESUMO
OBJECTIVES: Evidence of accelerated brain aging among HIV-infected adults argues for the increased risk of developing cerebral ß-amyloid (Aß) plaques. We compared the frequency of Aß plaque-bearing cases in our HIV cohort with that in a general cohort reported by Braak et al. We explored posttranslationally modified Aß forms (N3pE, E22P, phospho-Ser8) in plaques and E22P-Aß in the postmortem cerebrospinal fluid (CSF) in the HIV cohort. DESIGN: Clinicopathological study of HIV-infected adults. METHODS: To assess frontal Aß plaque deposition, we conducted immunohistochemistry for generic Aß (4G8) and three modified Aß forms. We determined CSF E22P-Aß levels by ELISA. RESULTS: We found 4G8-Aß plaques in 29% of 279 HIV-infected cases. Within the age range of 31-70 years, the frequency of 4G8-Aß plaque-bearing cases was higher in our HIV cohort (nâ=â273) compared with the general cohort (nâ=â1110) overall (29.3 vs. 25.8%) and across four age groups by decade (odds ratio 2.35, Pâ<â0.0001). In HIV-infected cases with (nâ=â37) and without (nâ=â12) 4G8-Aß plaques, modified Aß forms occurred in order: N3pE, E22P, and phospho-Ser8. In CSF assays of HIV-infected cases with (nâ=â27; 17 focal, 10 widespread) and without (nâ=â11) 4G8-Aß plaques, the median E22P-Aß/Aß40 ratio was higher among cases with widespread plaques than in cases with focal or absent plaques (Pâ=â0.047). CONCLUSION: Our findings suggest HIV-infected adults are at increased risk of developing cerebral Aß plaques. The occurrence of modified Aß forms in order suggests the progression stages of Aß plaque deposition. The potential for E22P-Aß as a CSF biomarker of cerebral Aß plaques should be investigated.