Common Transcriptional Signatures in Brain Tissue from Patients with HIV-Associated Neurocognitive Disorders, Alzheimer’s Disease, and Multiple Sclerosis

HIV-Associated Neurocognitive Disorders (HAND) is a common manifestation of HIV infection that afflicts about 50 % of HIV-positive individuals. As people with access to antiretroviral treatments live longer, HAND can be found in increasing segments of populations at risk for other chronic, neurodegenerative conditions such as Alzheimer’s disease (AD) and Multiple Sclerosis (MS). If brain diseases of diverse etiologies utilize similar biological pathways in the brain, they may coexist in a patient and possibly exacerbate neuropathogenesis and morbidity. To test this proposition, we conducted comparative meta-analysis of selected publicly available microarray datasets from brain tissues of patients with HAND, AD, and MS. In pair-wise and three-way analyses, we found a large number of dysregulated genes and biological processes common to either HAND and AD or HAND and MS, or to all three diseases. The common characteristic of all three diseases was up-regulation of broadly ranging immune responses in the brain. In addition, HAND and AD share down-modulation of processes involved, among others, in synaptic transmission and cell-cell signaling while HAND and MS share defective processes of neurogenesis and calcium/calmodulin-dependent protein kinase activity. Our approach could provide insight into the identification of common disease mechanisms and better intervention strategies for complex neurocognitive disorders.

[1]  Michael J. Taylor,et al.  HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy , 2010, Neurology.

[2]  Christopher M. Overall,et al.  Deciphering complex mechanisms in neurodegenerative diseases: the advent of systems biology , 2009, Trends in Neurosciences.

[3]  L. Pulliam.  HIV Regulation of Amyloid Beta Production , 2009, Journal of Neuroimmune Pharmacology.

[4]  A. Kablinger,et al.  HIV-associated dementia, Alzheimer's disease, multiple sclerosis, and schizophrenia: gene expression review , 2004, Journal of the Neurological Sciences.

[5]  L. Pulliam,et al.  P3-371 HIV-1 TAT inhibits neprilysin and elevates amyloid beta , 2004, Neurobiology of Aging.

[6]  Howard S. Fox,et al.  Patterns of gene dysregulation in the frontal cortex of patients with HIV encephalitis , 2004, Journal of Neuroimmunology.

[7]  L. Epstein,et al.  Neurologic manifestations of human immunodeficiency virus infection in children. , 1986, Pediatrics.

[8]  R. Tibshirani,et al.  Repeated observation of breast tumor subtypes in independent gene expression data sets , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[9]  D. Selkoe.  Alzheimer's Disease Is a Synaptic Failure , 2002, Science.

[10]  C. Kruse,et al.  Concerted changes in transcripts in the prefrontal cortex precede neuropathology in Alzheimer's disease. , 2010, Brain : a journal of neurology.

[11]  J. Corbeil,et al.  Diminished somatostatin gene expression in individuals with HIV and major depressive disorder , 2006, Neurology.

[12]  E. Masliah,et al.  Toll-like receptor pathway gene expression is associated with human immunodeficiency virus-associated neurodegeneration , 2011, Journal of NeuroVirology.

[13]  J. Alisky.  The coming problem of HIV-associated Alzheimer's disease. , 2007, Medical hypotheses.

[14]  M. Whittington,et al.  Long-Range–Projecting GABAergic Neurons Modulate Inhibition in Hippocampus and Entorhinal Cortex , 2012, Science.

[15]  D. Storm,et al.  The role of calmodulin as a signal integrator for synaptic plasticity , 2005, Nature Reviews Neuroscience.

[16]  Alejandra Borjabad,et al.  Gene Expression Profiles of HIV-1-Infected Glia and Brain: Toward Better Understanding of the Role of Astrocytes in HIV-1-Associated Neurocognitive Disorders , 2010, Journal of Neuroimmune Pharmacology.

[17]  Ben Crossett,et al.  First evidence of overlaps between HIV-Associated Dementia (HAD) and non-viral neurodegenerative diseases: proteomic analysis of the frontal cortex from HIV+ patients with and without dementia , 2010, Molecular Neurodegeneration.

[18]  R. Neve,et al.  Microarray Analysis of Hippocampal CA1 Neurons Implicates Early Endosomal Dysfunction During Alzheimer's Disease Progression , 2010, Biological Psychiatry.

[19]  L. Griffiths,et al.  Gene expression studies in multiple sclerosis. , 2007, Current genomics.

[20]  F. Fahrenholz,et al.  Differential gene expression in ADAM10 and mutant ADAM10 transgenic mice , 2009, BMC Genomics.

[21]  C. Vivar,et al.  Physiology and Pathology of Calcium Signaling in the Brain , 2012, Front. Pharmacol..

[22]  K. Ashe,et al.  Tau Mislocalization to Dendritic Spines Mediates Synaptic Dysfunction Independently of Neurodegeneration , 2010, Neuron.

[23]  J. Becker,et al.  Updated research nosology for HIV-associated neurocognitive disorders , 2007, Neurology.

[24]  A. Pitkänen,et al.  Large-Scale Analysis of Gene Expression in Epilepsy Research: Is Synthesis Already Possible? , 2004, Neurochemical Research.

[25]  V. Haroutunian,et al.  Gene Expression Alterations in the Sphingolipid Metabolism Pathways during Progression of Dementia and Alzheimer’s Disease: A Shift Toward Ceramide Accumulation at the Earliest Recognizable Stages of Alzheimer’s Disease? , 2007, Neurochemical Research.

[26]  Jianhui Zhong,et al.  Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment , 2011, AIDS.

[27]  R. Lempicki,et al.  Evaluation of gene expression measurements from commercial microarray platforms. , 2003, Nucleic acids research.

[28]  B. Navia,et al.  The acquired immunodeficiency syndrome dementia complex as the presenting or sole manifestation of human immunodeficiency virus infection. , 1987, Archives of neurology.

[29]  A. Minagar,et al.  The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis , 2002, Journal of the Neurological Sciences.

[30]  P. Avner,et al.  Interaction between nucleosome assembly protein 1-like family members. , 2011, Journal of molecular biology.

[31]  R. Rudick,et al.  Activation of the ciliary neurotrophic factor (CNTF) signalling pathway in cortical neurons of multiple sclerosis patients. , 2007, Brain : a journal of neurology.

[32]  R. Rudick,et al.  Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients , 2006, Annals of neurology.

[33]  L. Barbeito,et al.  The molecular bases of Alzheimer's disease and other neurodegenerative disorders. , 2001, Archives of medical research.

[34]  G. Pasinetti,et al.  Use of cDNA microarray in the search for molecular markers involved in the onset of Alzheimer's disease dementia , 2001, Journal of neuroscience research.

[35]  J. Hoheisel.  Microarray technology: beyond transcript profiling and genotype analysis , 2006, Nature Reviews Microbiology.

[36]  Joseph White,et al.  Comparative gene expression analysis in mouse models for multiple sclerosis, Alzheimer's disease and stroke for identifying commonly regulated and disease-specific gene changes. , 2010, Genomics.

[37]  L. Kappos,et al.  Transcriptional profiling of multiple sclerosis: towards improved diagnosis and treatment , 2006, Expert review of molecular diagnostics.

[38]  B. Navia,et al.  The AIDS dementia complex: II. Neuropathology , 1986, Annals of neurology.

[39]  Ludwig Kappos,et al.  Multiple sclerosis as a generalized CNS disease—comparative microarray analysis of normal appearing white matter and lesions in secondary progressive MS , 2004, Journal of Neuroimmunology.

[40]  C. Moussa,et al.  Inflammation in the early stages of neurodegenerative pathology , 2011, Journal of Neuroimmunology.

[41]  L. Prockop.  AIDS dementia complex. , 1988, The Journal of legal medicine.

[42]  S. DeKosky,et al.  Alpha7 nicotinic receptor up-regulation in cholinergic basal forebrain neurons in Alzheimer disease. , 2007, Archives of neurology.

[43]  W. Klein,et al.  Aβ Oligomer-Induced Synapse Degeneration in Alzheimer’s Disease , 2011, Cellular and Molecular Neurobiology.

[44]  P. Eikelenboom,et al.  Source (or Part of the following Source): Type Article Title Neuroinflammation in Alzheimer's Disease Wanes with Age Author(s) Neuroinflammation in Alzheimer's Disease Wanes with Age , 2022 .

[45]  R. Lenkinski,et al.  Biochemical changes in the frontal lobe of HIV-infected individuals detected by magnetic resonance spectroscopy. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[46]  K. Davis,et al.  Large-scale microarray studies of gene expression in multiple regions of the brain in schizophrenia and Alzheimer's disease. , 2005, International review of neurobiology.

[47]  Douglas A. Hosack,et al.  Identifying biological themes within lists of genes with EASE , 2003, Genome Biology.

[48]  A. Beaudet,et al.  Altered Ultrasonic Vocalization and Impaired Learning and Memory in Angelman Syndrome Mouse Model with a Large Maternal Deletion from Ube3a to Gabrb3 , 2010, PloS one.

[49]  J. Corbeil,et al.  Methamphetamine stimulates interferon inducible genes in HIV infected brain , 2005, Journal of Neuroimmunology.

[50]  Yaakov Stern,et al.  HIV-associated cognitive impairment before and after the advent of combination therapy , 2011, Journal of NeuroVirology.

[51]  R. Price,et al.  The AIDS dementia complex. , 1988, The Journal of infectious diseases.

[52]  L. Griffiths,et al.  Quantitative and qualitative changes in gene expression patterns characterize the activity of plaques in multiple sclerosis. , 2003, Brain research. Molecular brain research.

[53]  L. Hersh,et al.  BACE2 expression increases in human neurodegenerative disease. , 2012, The American journal of pathology.

[54]  Dianne Langford,et al.  HIV and antiretroviral therapy in the brain: neuronal injury and repair , 2008, Nature Reviews Neuroscience.

[55]  Douglas D. Richman,et al.  HIV chemotherapy : AIDS , 2001 .

[56]  Allan R. Jones,et al.  An anatomically comprehensive atlas of the adult human brain transcriptome , 2012, Nature.

[57]  Giovanni Parmigiani,et al.  A Cross-Study Comparison of Gene Expression Studies for the Molecular Classification of Lung Cancer , 2004, Clinical Cancer Research.

[58]  B. Ross,et al.  Evidence of reduced glutamate in the frontal lobe of HIV‐seropositive patients , 2009, NMR in biomedicine.

[59]  P. Riederer,et al.  Comparison analysis of gene expression patterns between sporadic Alzheimer's and Parkinson's disease. , 2007, Journal of Alzheimer's disease : JAD.

[60]  H. Hartung,et al.  Animal models of multiple sclerosis—Potentials and limitations , 2010, Progress in Neurobiology.

[61]  R. Reynolds,et al.  Molecular Changes in Normal Appearing White Matter in Multiple Sclerosis are Characteristic of Neuroprotective Mechanisms Against Hypoxic Insult , 2003, Brain pathology.

[62]  Byungkyu Brian Park,et al.  Modeling the interactions of Alzheimer-related genes from the whole brain microarray data and diffusion tensor images of human brain , 2012, BMC Bioinformatics.

[63]  Marlene Kropp,et al.  The expression profile of the tumor suppressor gene Lzts1 suggests a role in neuronal development , 2012, Developmental dynamics : an official publication of the American Association of Anatomists.

[64]  Shao-ming Lu,et al.  The Phospholipid Mediator Platelet-Activating Factor Mediates Striatal Synaptic Facilitation , 2007, Journal of Neuroimmune Pharmacology.

[65]  L. Steinman,et al.  Transcriptional analysis of targets in multiple sclerosis , 2003, Nature Reviews Immunology.

[66]  Jean-Marie Annoni,et al.  Cognitive dysfunction in HIV patients despite long-standing suppression of viremia , 2009, AIDS.

[67]  I. Ferrer,et al.  Neuronal hemoglobin is reduced in Alzheimer's disease, argyrophilic grain disease, Parkinson's disease, and dementia with Lewy bodies. , 2011, Journal of Alzheimer's disease : JAD.

[68]  David J. Volsky,et al.  Significant Effects of Antiretroviral Therapy on Global Gene Expression in Brain Tissues of Patients with HIV-1-Associated Neurocognitive Disorders , 2011, PLoS pathogens.

[69]  Sam Richman,et al.  An online database for brain disease research , 2006, BMC Genomics.

[70]  W. Markesbery,et al.  Incipient Alzheimer's disease: Microarray correlation analyses reveal major transcriptional and tumor suppressor responses , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[71]  J. Eberwine,et al.  Expression Profile Analysis of Neurodegenerative Disease: Advances in Specificity and Resolution , 2004, Neurochemical Research.

[72]  W. L. Benedict,et al.  Multiple Sclerosis , 2007, Journal - Michigan State Medical Society.

[73]  E. Grünblatt.  The benefits of microarrays as tools for studying neuropsychiatric disorders. , 2004, Drugs of today.

[74]  C. Cotman,et al.  Inflammatory changes parallel the early stages of Alzheimer disease , 2007, Neurobiology of Aging.

[75]  E. Jazin,et al.  Alzheimer's disease: mRNA expression profiles of multiple patients show alterations of genes involved with calcium signaling , 2006, Neurobiology of Disease.

[76]  S. Cavallaro,et al.  Genomic Portraits of the Nervous System in Health and Disease , 2004, Neurochemical Research.

[77]  R. Reynolds,et al.  The neuropathological basis of clinical progression in multiple sclerosis , 2011, Acta Neuropathologica.

[78]  B. Cubelos,et al.  Cux1 and Cux2 Regulate Dendritic Branching, Spine Morphology, and Synapses of the Upper Layer Neurons of the Cortex , 2010, Neuron.

[79]  A. Minagar,et al.  Alzheimer's disease and HIV associated dementia related genes: I. location and function , 2008, Bioinformation.

[80]  L. Siever,et al.  A system-level transcriptomic analysis of schizophrenia using postmortem brain tissue samples. , 2012, Archives of general psychiatry.

[81]  Soo‐Young Choi,et al.  Analysis of differentially expressed genes in early- and late-stage APPsw-transgenic and normal mice using cDNA microarray. , 2007, International journal of molecular medicine.

[82]  Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways , 2012, Journal of Neuroinflammation.

[83]  M. Ball,et al.  Gene expression profiling of 12633 genes in Alzheimer hippocampal CA1: Transcription and neurotrophic factor down‐regulation and up‐regulation of apoptotic and pro‐inflammatory signaling , 2002, Journal of neuroscience research.

[84]  Douglas D. Richman,et al.  HIV chemotherapy , 2001, Nature.

[85]  M. Jucker,et al.  Pathogenic protein seeding in alzheimer disease and other neurodegenerative disorders , 2011, Annals of neurology.

[86]  B. Lu,et al.  Synapses and Dendritic Spines as Pathogenic Targets in Alzheimer's Disease , 2012, Neural plasticity.

[87]  E. Major,et al.  Relapsing and remitting human immunodeficiency virus—associated leukoencephalomyelopathy , 1992, Annals of neurology.

[88]  A. Minagar,et al.  Analytic approaches to differential gene expression in AIDS versus control brains. , 2004, Frontiers in bioscience : a journal and virtual library.

[89]  Justin C McArthur,et al.  The prevalence and incidence of neurocognitive impairment in the HAART era , 2007, AIDS.

[90]  N. Schaeren-Wiemers,et al.  RNA profiling of MS brain tissues. , 2008, International MS journal.

[91]  D. Hoffman,et al.  DPP6 Establishes the A-Type K+ Current Gradient Critical for the Regulation of Dendritic Excitability in CA1 Hippocampal Neurons , 2011, Neuron.

[92]  Howard E. Gendelman,et al.  Dementia Associated with the Acquired Immunodeficiency Syndrome , 1995 .

[93]  D. Salomon,et al.  Early dysregulation of cripto-1 and immunomodulatory genes in the cerebral cortex in a macaque model of neuroAIDS , 2006, Neuroscience Letters.

[94]  C. Eggers,et al.  Antibodies to myelin oligodendrocyte glycoprotein in HIV-1 associated neurocognitive disorder: a cross-sectional cohort study , 2010, Journal of Neuroinflammation.

[95]  M. Rattray,et al.  Gene expression profiling in human neurodegenerative disease , 2012, Nature Reviews Neurology.

[96]  B. Navia,et al.  The AIDS dementia complex: I. Clinical features , 1986, Annals of neurology.

[97]  D. Ehrnhoefer,et al.  Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development , 2011, Nature Reviews Drug Discovery.

[98]  M. García-Villanueva,et al.  Focal Monophasic Demyelinating Leukoencephalopathy in Advanced HIV Infection , 2004, European Neurology.

[99]  Lynn Pulliam,et al.  HIV-1 Tat inhibits neprilysin and elevates amyloid β , 2005 .

[100]  B. Gelman,et al.  Acquired neuronal channelopathies in HIV-associated dementia , 2004, Journal of Neuroimmunology.

[101]  Shao-Ming Lu,et al.  HIV-1 Tat-Induced Microgliosis and Synaptic Damage via Interactions between Peripheral and Central Myeloid Cells , 2011, PloS one.

[102]  Julio J. Valdés,et al.  Permission is granted to quote short excerpts and to reproduce figures and tables from this report, provided that the source of such material is fully acknowledged. Data Mining of Gene Expression Changes in , 2003 .

[103]  V. Steen,et al.  Upregulation of Immunoglobulin‐related Genes in Cortical Sections from Multiple Sclerosis Patients , 2009, Brain pathology.

[104]  A. Stromberg,et al.  Harnessing the power of gene microarrays for the study of brain aging and Alzheimer's disease: Statistical reliability and functional correlation , 2005, Ageing Research Reviews.

[105]  M. Starkey,et al.  Gene expression profiles of metabolic enzyme transcripts in Alzheimer's disease , 2007, Brain Research.

[106]  B. Trapp,et al.  Gene expression profiling in multiple sclerosis brain , 2012, Neurobiology of Disease.