Long-term HIV-1 Tat Expression in the Brain Led to Neurobehavioral, Pathological, and Epigenetic Changes Reminiscent of Accelerated Aging
Xiaojie Zhao1, Yan Fan2, Philip H. Vann2, Jessica M. Wong2, Nathalie Sumien2, Johnny J. He1,*
1Department of Microbiology, Immunology & Genetics and 2Department of Pharmacology & Neuroscience, Graduate School of Biomedical Sciences, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
HIV infects the central nervous system and causes HIV/neuroAIDS, which is predominantly manifested in the form of mild cognitive and motor disorder in the era of combination antiretroviral therapy. HIV Tat protein is known to be a major pathogenic factor for HIV/neuroAIDS through a myriad of direct and indirect mechanisms. However, most, if not all of studies involve short-time exposure of recombinant Tat protein in vitro or short-term Tat expression in vivo. In this study, we took advantage of the doxycycline-inducible brain-specific HIV-1 Tat transgenic mouse model, fed the animals for 12 months, and assessed behavioral, pathological, and epigenetic changes in these mice. Long-term Tat expression led to poorer short-and long-term memory, lower locomotor activity and impaired coordination and balance ability, increased astrocyte activation and compromised neuronal integrity, and decreased global genomic DNA methylation. There were sex- and brain region-dependent differences in behaviors, pathologies, and epigenetic changes resulting from long-term Tat expression. All these changes are reminiscent of accelerated aging, raising the possibility that HIV Tat contributes, at least in part, to HIV infection-associated accelerated aging in HIV-infected individuals. These findings also suggest another utility of this model for HIV infection-associated accelerated aging studies.
Xiaojie Zhao,Yan Fan,Philip H. Vann, et al. Long-term HIV-1 Tat Expression in the Brain Led to Neurobehavioral, Pathological, and Epigenetic Changes Reminiscent of Accelerated Aging[J]. Aging and disease,
2020, 11(1): 93-107.
Figure 1. Spatial memory of iTat mice by Morris water maze (MWZ). Wild-type (Wt) and iTat mice of 21 days old were fed with Dox-containing food pellets for 12 months and their short- and long-term spatial memory were determined. (A) Scheme of MWZ test. Mice underwent pre-training for 2 days, then training every day and probe test (marked by thin arrows) every other day, and the data in last probe test (Day 13) was analyzed to determine short-term spatial memory. After 7 days, the mice underwent another probe test (marked by a thick arrow) on day 18 to determine long-term spatial memory. (B and C) iTat short-term spatial memory (B) and long-term spatial memory (C). Mice were grouped into males and females and assessed for spatial memory based on the Time at target quadrant % (I), Distance to target quadrant (II), Time at platform site % (III), Distance in platform site (IV), Platform entries (V), and Speed (VI). The number of mice in each group was shown in the bar.
Figure 2. Locomotor activity of iTat mice by open field test. The mice were placed into an open chamber and their movement was recorded for 10 min. The trace was analyzed for total travel distance (A) and travel speed (B). The number of mice in each group was shown in the bar.
Figure 3. Motor coordination and balance ability of iTat mice by bridge walk test. The mice were placed into different types of raised beams, and the latency to fall from the beam was determined. The task was carried out with increasing difficulties and in the order of large square (LS), large round (LR), small square (SS), and small round (SR). The number of mice in each group was shown in the bar.
Figure 4. Expression of GFAP, SYP and PSD95 in the brain of iTat mice. Cortex (CORT, A), cerebellum (CERE, B), hippocampus (HIP, C) and caudate putamen (CPU, D) of the mice were dissected, homogenized for lysates, and analyzed for expression of GFAP, SYP and PSD95, by Western blotting. β-actin was used as an equal loading control. Six mice in each group were used for the analysis and three of them were randomly selected from the same SDS-PAGE for presentation. Protein expression in each group was normalized by Wt males and the relative level was shown at the right of the respective blots.
Probe test Day
Table 1 Latency to platform within 30s.
Figure 5. DNA Methyltransferase expression and genomic DNA methylation in the brain of iTat mice. qPT-PCR was used to screen the mRNA expression of DNMT1 (A-I) DNMT3A (A-II) and DNMT3B (A-III) in whole brain lysates, followed by Western blots to determine DNMT3B expression in different brain regions including CORT, CERE, HIP and CPU (two close bands were recognized by DNMT3B antibody in some brain regions) (B). Next, two brain regions, CORT and CERE, were selected to elucidate the genomic DNA methylation level by 5-methylcytosine ELISA. The number of mice was shown in the bar, except for Western blots where six mice were used in every group and three were randomly selected from the same SDS-PAGE for presentation. All data was normalized by Wt males and shown as a relative level. The internal control of Western blots in (B) was β-actin which was same to figure 4 in different brain regions.
Male iTat vs Wt
Female iTat vs Wt
Total Male vs Female
Table 2 Summary of comparisons between different mice/sex and different brain regions.
Price RW, Brew B, Sidtis J, Rosenblum M, Scheck AC, Cleary P (1988). The brain in AIDS: central nervous system HIV-1 infection and AIDS dementia complex. Science, 239:586-592.
Brew BJ (2009). HIV, the brain, children, HAART and 'neuro-HAART': a complex mix. AIDS, 23:1909-1910.
Cohen RA, Gongvatana A (2009). HIV-associated brain dysfunction in the era of HAART: reasons for hope, but continued concern. Neurology, 73:338-339.
Sacktor N (2002). The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy. J Neurovirol, 8 Suppl 2:115-121.
Lee SC, Hatch WC, Liu W, Brosnan CF, Dickson DW (1993). Productive infection of human fetal microglia in vitro by HIV-1. Ann N Y Acad Sci, 693:314-316.
Tornatore C, Chandra R, Berger JR, Major EO (1994). HIV-1 infection of subcortical astrocytes in the pediatric central nervous system. Neurology, 44:481-487.
Schweighardt B, Atwood WJ (2001). HIV type 1 infection of human astrocytes is restricted by inefficient viral entry. AIDS Res Hum Retroviruses, 17:1133-1142.
Gorry P, Purcell D, Howard J, McPhee D (1998). Restricted HIV-1 infection of human astrocytes: potential role of nef in the regulation of virus replication. J Neurovirol, 4:377-386.
Saito Y, Sharer LR, Epstein LG, Michaels J, Mintz M, Louder M, et al. (1994). Overexpression of nef as a marker for restricted HIV-1 infection of astrocytes in postmortem pediatric central nervous tissues. Neurology, 44:474-481.
Liu Y, Liu H, Kim BO, Gattone VH, Li J, Nath A, et al. (2004). CD4-independent infection of astrocytes by human immunodeficiency virus type 1: requirement for the human mannose receptor. J Virol, 78:4120-4133.
Hudson L, Liu J, Nath A, Jones M, Raghavan R, Narayan O, et al. (2000). Detection of the human immunodeficiency virus regulatory protein tat in CNS tissues. J Neurovirol, 6:145-155.
Johnson TP, Patel K, Johnson KR, Maric D, Calabresi PA, Hasbun R, et al. (2013). Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. Proc Natl Acad Sci U S A, 110:13588-13593.
Brack-Werner R (1999). Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. AIDS, 13:1-22.
Bagasra O, Lavi E, Bobroski L, Khalili K, Pestaner JP, Tawadros R, et al. (1996). Cellular reservoirs of HIV-1 in the central nervous system of infected individuals: identification by the combination of in situ polymerase chain reaction and immunohistochemistry. AIDS, 10:573-585.
Frankel AD, Pabo CO (1988). Cellular uptake of the tat protein from human immunodeficiency virus. Cell, 55:1189-1193.
Helland DE, Welles JL, Caputo A, Haseltine WA (1991). Transcellular transactivation by the human immunodeficiency virus type 1 tat protein. J Virol, 65:4547-4549.
Liu Y, Jones M, Hingtgen CM, Bu G, Laribee N, Tanzi RE, et al. (2000). Uptake of HIV-1 tat protein mediated by low-density lipoprotein receptor-related protein disrupts the neuronal metabolic balance of the receptor ligands. Nat Med, 6:1380-1387.
Norman JP, Perry SW, Kasischke KA, Volsky DJ, Gelbard HA (2007). HIV-1 trans activator of transcription protein elicits mitochondrial hyperpolarization and respiratory deficit, with dysregulation of complex IV and nicotinamide adenine dinucleotide homeostasis in cortical neurons. J Immunol, 178:869-876.
Caporello E, Nath A, Slevin J, Galey D, Hamilton G, Williams L, et al. (2006). The immunophilin ligand GPI1046 protects neurons from the lethal effects of the HIV-1 proteins gp120 and Tat by modulating endoplasmic reticulum calcium load. J Neurochem, 98:146-155.
Brailoiu E, Brailoiu GC, Mameli G, Dolei A, Sawaya BE, Dun NJ (2006). Acute exposure to ethanol potentiates human immunodeficiency virus type 1 Tat-induced Ca(2+) overload and neuronal death in cultured rat cortical neurons. J Neurovirol, 12:17-24.
KrumanII, Nath A, Mattson MP (1998). HIV-1 protein Tat induces apoptosis of hippocampal neurons by a mechanism involving caspase activation, calcium overload, and oxidative stress. Exp Neurol, 154:276-288.
Orsini MJ, Debouck CM, Webb CL, Lysko PG (1996). Extracellular human immunodeficiency virus type 1 Tat protein promotes aggregation and adhesion of cerebellar neurons. J Neurosci, 16:2546-2552.
Aprea S, Del Valle L, Mameli G, Sawaya BE, Khalili K, Peruzzi F (2006). Tubulin-mediated binding of human immunodeficiency virus-1 Tat to the cytoskeleton causes proteasomal-dependent degradation of microtubule-associated protein 2 and neuronal damage. J Neurosci, 26:4054-4062.
Albini A, Benelli R, Giunciuglio D, Cai T, Mariani G, Ferrini S, et al. (1998). Identification of a novel domain of HIV tat involved in monocyte chemotaxis. J Biol Chem, 273:15895-15900.
Benelli R, Barbero A, Ferrini S, Scapini P, Cassatella M, Bussolino F, et al. (2000). Human immunodeficiency virus transactivator protein (Tat) stimulates chemotaxis, calcium mobilization, and activation of human polymorphonuclear leukocytes: implications for Tat-mediated pathogenesis. J Infect Dis, 182:1643-1651.
de Paulis A, De Palma R, Di Gioia L, Carfora M, Prevete N, Tosi G, et al. (2000). Tat protein is an HIV-1-encoded beta-chemokine homolog that promotes migration and up-regulates CCR3 expression on human Fc epsilon RI+ cells. J Immunol, 165:7171-7179.
Lafrenie RM, Wahl LM, Epstein JS, Hewlett IK, Yamada KM, Dhawan S (1996). HIV-1-Tat protein promotes chemotaxis and invasive behavior by monocytes. J Immunol, 157:974-977.
Park IW, Wang JF, Groopman JE (2001). HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes. Blood, 97:352-358.
Jones M, Olafson K, Del Bigio MR, Peeling J, Nath A (1998). Intraventricular injection of human immunodeficiency virus type 1 (HIV-1) tat protein causes inflammation, gliosis, apoptosis, and ventricular enlargement. J Neuropathol Exp Neurol, 57:563-570.
Eugenin E, King J, Nath A, Calderon M, Zukin R, Bennett M, et al. (2007). HIV-tat induces formation of an LRP-PSD-95- NMDAR-nNOS complex that promotes apoptosis in neurons and astrocytes. Proc Natl Acad Sci U S A:3438-3443.
Peruzzi F (2006). The multiple functions of HIV-1 Tat: proliferation versus apoptosis. Front Biosci, 11:708-717.
Kim BO, Liu Y, Ruan Y, Xu ZC, Schantz L, He JJ (2003). Neuropathologies in transgenic mice expressing human immunodeficiency virus type 1 Tat protein under the regulation of the astrocyte-specific glial fibrillary acidic protein promoter and doxycycline. Am J Pathol, 162:1693-1707.
Chauhan A, Turchan J, Pocernich C, Bruce-Keller A, Roth S, Butterfield DA, et al. (2003). Intracellular human immunodeficiency virus Tat expression in astrocytes promotes astrocyte survival but induces potent neurotoxicity at distant sites via axonal transport. J Biol Chem, 278:13512-13519.
Zhou BY, He JJ (2004). Proliferation inhibition of astrocytes, neurons, and non-glial cells by HIV-1 Tat protein. Neuroscience Letters, 359:155-158.
Zhou BY, Liu Y, Kim B, Xiao Y, He JJ (2004). Astrocyte activation and dysfunction and neuron death by HIV-1 Tat expression in astrocytes. Mol Cell Neurosci, 27:296-305.
Zhong Y, Hennig B, Toborek M (2009). Intact lipid rafts regulate HIV-1 Tat protein-induced activation of the Rho signaling and upregulation of P-glycoprotein in brain endothelial cells. J Cereb Blood Flow Metab, 30: 522-533.
Andras IE, Rha G, Huang W, Eum S, Couraud PO, Romero IA, et al. (2008). Simvastatin protects against amyloid beta and HIV-1 Tat-induced promoter activities of inflammatory genes in brain endothelial cells. Mol Pharmacol, 73:1424-1433.
Price TO, Uras F, Banks WA, Ercal N (2006). A novel antioxidant N-acetylcysteine amide prevents gp120- and Tat-induced oxidative stress in brain endothelial cells. Exp Neurol, 201:193-202.
Andras IE, Pu H, Tian J, Deli MA, Nath A, Hennig B, et al. (2005). Signaling mechanisms of HIV-1 Tat-induced alterations of claudin-5 expression in brain endothelial cells. J Cereb Blood Flow Metab, 25:1159-1170.
Avraham HK, Jiang S, Lee TH, Prakash O, Avraham S (2004). HIV-1 Tat-mediated effects on focal adhesion assembly and permeability in brain microvascular endothelial cells. J Immunol, 173:6228-6233.
Khan NA, Di Cello F, Nath A, Kim KS (2003). Human immunodeficiency virus type 1 tat-mediated cytotoxicity of human brain microvascular endothelial cells. J Neurovirol, 9:584-593.
Kim TA, Avraham HK, Koh YH, Jiang S, Park IW, Avraham S (2003). HIV-1 Tat-mediated apoptosis in human brain microvascular endothelial cells. J Immunol, 170:2629-2637.
Hofman FM, Chen P, Incardona F, Zidovetzki R, Hinton DR (1999). HIV-1 tat protein induces the production of interleukin-8 by human brain-derived endothelial cells. J Neuroimmunol, 94:28-39.
Toborek M, Lee YW, Pu H, Malecki A, Flora G, Garrido R, et al. (2003). HIV-Tat protein induces oxidative and inflammatory pathways in brain endothelium. J Neurochem, 84:169-179.
Dayton AI, Sodroski JG, Rosen CA, Goh WC, Haseltine WA (1986). The trans-activator gene of the human T cell lymphotropic virus type III is required for replication. Cell, 44:941-947.
Kolson DL, Buchhalter J, Collman R, Hellmig B, Farrell CF, Debouck C, et al. (1993). HIV-1 Tat alters normal organization of neurons and astrocytes in primary rodent brain cell cultures: RGD sequence dependence. AIDS Res Hum Retroviruses, 9:677-685.
Conant K, Garzino-Demo A, Nath A, McArthur JC, Halliday W, Power C, et al. (1998). Induction of monocyte chemoattractant protein-1 in HIV-1 Tat-stimulated astrocytes and elevation in AIDS dementia. Proc Natl Acad Sci U S A, 95:3117-3121.
Nath A, Conant K, Chen P, Scott C, Major EO (1999). Transient exposure to HIV-1 Tat protein results in cytokine production in macrophages and astrocytes. A hit and run phenomenon. J Biol Chem, 274:17098-17102.
El-Hage N, Gurwell JA, Singh IN, Knapp PE, Nath A, Hauser KF (2005). Synergistic increases in intracellular Ca2+, and the release of MCP-1, RANTES, and IL-6 by astrocytes treated with opiates and HIV-1 Tat. Glia, 50:91-106.
Williams R, Yao H, Dhillon NK, Buch SJ (2009). HIV-1 Tat co-operates with IFN-gamma and TNF-alpha to increase CXCL10 in human astrocytes. PLoS One, 4:e5709.
Zhou BY, He JJ (2004). Proliferation inhibition of astrocytes, neurons, and non-glial cells by intracellularly expressed human immunodeficiency virus type 1 (HIV-1) Tat protein. Neurosci Lett, 359:155-158.
Zou W, Kim BO, Zhou BY, Liu Y, Messing A, He JJ (2007). Protection against human immunodeficiency virus type 1 Tat neurotoxicity by Ginkgo biloba extract EGb 761 involving glial fibrillary acidic protein. Am J Pathol, 171:1923-1935.
Fan Y, Zou W, Green LA, Kim BO, He JJ (2011). Activation of Egr-1 expression in astrocytes by HIV-1 Tat: new insights into astrocyte-mediated Tat neurotoxicity. J Neuroimmune Pharmacol, 6:121-129.
Zou W, Wang Z, Liu Y, Fan Y, Zhou BY, Yang XF, et al. (2010). Involvement of p300 in constitutive and HIV-1 Tat-activated expression of glial fibrillary acidic protein in astrocytes. Glia, 58:1640-1648.
Fields J, Dumaop W, Eleuteri S, Campos S, Serger E, Trejo M, et al. (2015). HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders. J Neurosci, 35:1921-1938.
Fan Y, Gao X, Chen J, Liu Y, He JJ (2016). HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway. J Neurosci, 36:11362-11373.
Fan Y, He JJ (2016). HIV-1 Tat Promotes Lysosomal Exocytosis in Astrocytes and Contributes to Astrocyte-mediated Tat Neurotoxicity. J Biol Chem, 291:22830-22840.
Fan Y, He JJ (2016). HIV-1 Tat Induces Unfolded Protein Response and Endoplasmic Reticulum Stress in Astrocytes and Causes Neurotoxicity through Glial Fibrillary Acidic Protein (GFAP) Activation and Aggregation. J Biol Chem, 291:22819-22829.
Rahimian P, He JJ (2016). HIV-1 Tat-shortened neurite outgrowth through regulation of microRNA-132 and its target gene expression. J Neuroinflammation, 13:247.
Raybuck JD, Hargus NJ, Thayer SA (2017). A GluN2B-Selective NMDAR Antagonist Reverses Synapse Loss and Cognitive Impairment Produced by the HIV-1 Protein Tat. J Neurosci, 37:7837-7847.
Kesby JP, Markou A, Semenova S (2016). The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice. Neuropharmacology, 109:205-215.
Nookala AR, Schwartz DC, Chaudhari NS, Glazyrin A, Stephens EB, Berman NEJ, et al. (2018). Methamphetamine augment HIV-1 Tat mediated memory deficits by altering the expression of synaptic proteins and neurotrophic factors. Brain Behav Immun, 71:37-51.
Carey AN, Sypek EI, Singh HD, Kaufman MJ, McLaughlin JP (2012). Expression of HIV-Tat protein is associated with learning and memory deficits in the mouse. Behav Brain Res, 229:48-56.
Li ST, Matsushita M, Moriwaki A, Saheki Y, Lu YF, Tomizawa K, et al. (2004). HIV-1 Tat inhibits long-term potentiation and attenuates spatial learning [corrected]. Ann Neurol, 55:362-371.
Paris JJ, Singh HD, Carey AN, McLaughlin JP (2015). Exposure to HIV-1 Tat in brain impairs sensorimotor gating and activates microglia in limbic and extralimbic brain regions of male mice. Behav Brain Res, 291:209-218.
Moran LM, Fitting S, Booze RM, Webb KM, Mactutus CF (2014). Neonatal intrahippocampal HIV-1 protein Tat(1-86) injection: neurobehavioral alterations in the absence of increased inflammatory cytokine activation. Int J Dev Neurosci, 38:195-203.
Hahn YK, Podhaizer EM, Farris SP, Miles MF, Hauser KF, Knapp PE (2015). Effects of chronic HIV-1 Tat exposure in the CNS: heightened vulnerability of males versus females to changes in cell numbers, synaptic integrity, and behavior. Brain Struct Funct, 220:605-623.
Paris JJ, Singh HD, Ganno ML, Jackson P, McLaughlin JP (2014). Anxiety-like behavior of mice produced by conditional central expression of the HIV-1 regulatory protein, Tat. Psychopharmacology (Berl), 231:2349-2360.
Fu X, Lawson MA, Kelley KW, Dantzer R (2011). HIV-1 Tat activates indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures in a p38 mitogen-activated protein kinase-dependent manner. J Neuroinflammation, 8:88.
Langford D, Oh Kim B, Zou W, Fan Y, Rahimain P, Liu Y, et al. (2018). Doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) as an HIV/neuroAIDS model. J Neurovirol, 24:168-179.
Sumien N, Sims MN, Taylor HJ, Forster MJ (2006). Profiling psychomotor and cognitive aging in four-way cross mice. Age (Dordr), 28:265-282.
Fields JA, Metcalf J, Overk C, Adame A, Spencer B, Wrasidlo W, et al. (2017). The anticancer drug sunitinib promotes autophagyand protects from neurotoxicity in an HIV-1 Tat model of neurodegeneration. J Neurovirol, 23:290-303.
Fang JY, Mikovits JA, Bagni R, Petrow-Sadowski CL, Ruscetti FW (2001). Infection of lymphoid cells by integration-defective human immunodeficiency virus type 1 increases de novo methylation. J Virol, 75:9753-9761.
Luzzi A, Morettini F, Gazaneo S, Mundo L, Onnis A, Mannucci S, et al. (2014). HIV-1 Tat induces DNMT over-expression through microRNA dysregulation in HIV-related non Hodgkin lymphomas. Infect Agent Cancer, 9:41.
Koss WA, Frick KM (2017). Sex differences in hippocampal function. J Neurosci Res, 95:539-562.
Benice TS, Rizk A, Kohama S, Pfankuch T, Raber J (2006). Sex-differences in age-related cognitive decline in C57BL/6J mice associated with increased brain microtubule-associated protein 2 and synaptophysin immunoreactivity. Neuroscience, 137:413-423.
Diaz Brinton R (2012). Minireview: translational animal models of human menopause: challenges and emerging opportunities. Endocrinology, 153:3571-3578.
Frick KM (2009). Estrogens and age-related memory decline in rodents: what have we learned and where do we go from here? Horm Behav, 55:2-23.
McFadyen MP, Kusek G, Bolivar VJ, Flaherty L (2003). Differences among eight inbred strains of mice in motor ability and motor learning on a rotorod. Genes Brain Behav, 2:214-219.
Kovacs AD, Pearce DA (2013). Location- and sex-specific differences in weight and motor coordination in two commonly used mouse strains. Sci Rep, 3:2116.
McLaurin KA, Booze RM, Mactutus CF, Fairchild AJ (2017). Sex Matters: Robust Sex Differences in Signal Detection in the HIV-1 Transgenic Rat. Front Behav Neurosci, 11:212.
Schier CJ, Marks WD, Paris JJ, Barbour AJ, McLane VD, Maragos WF, et al. (2017). Selective Vulnerability of Striatal D2 versus D1 Dopamine Receptor-Expressing Medium Spiny Neurons in HIV-1 Tat Transgenic Male Mice. J Neurosci, 37:5758-5769.
Goodall EF, Wang C, Simpson JE, Baker DJ, Drew DR, Heath PR, et al. (2018). Age-associated changes in the blood-brain barrier: comparative studies in human and mouse. Neuropathol Appl Neurobiol, 44:328-340.
Rogers JT, Liu CC, Zhao N, Wang J, Putzke T, Yang L, et al. (2017). Subacute ibuprofen treatment rescues the synaptic and cognitive deficits in advanced-aged mice. Neurobiol Aging, 53:112-121.
Chepkova AN, Schonfeld S, Sergeeva OA (2015). Age-related alterations in the expression of genes and synaptic plasticity associated with nitric oxide signaling in the mouse dorsal striatum. Neural Plast, 2015:458123.
Rodriguez JJ, Yeh CY, Terzieva S, Olabarria M, Kulijewicz-Nawrot M, Verkhratsky A (2014). Complex and region-specific changes in astroglial markers in the aging brain. Neurobiol Aging, 35:15-23.
Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. (2017). Neurotoxic reactive astrocytes are induced by activated microglia. Nature, 541:481-487.
Savioz A, Leuba G, Vallet PG (2014). A framework to understand the variations of PSD-95 expression in brain aging and in Alzheimer's disease. Ageing Res Rev, 18:86-94.
Kumar D, Thakur MK (2015). Age-related expression of Neurexin1 and Neuroligin3 is correlated with presynaptic density in the cerebral cortex and hippocampus of male mice. Age (Dordr), 37:17.
Calhoun ME, Kurth D, Phinney AL, Long JM, Hengemihle J, Mouton PR, et al. (1998). Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice. Neurobiol Aging, 19:599-606.
Fitting S, Ignatowska-Jankowska BM, Bull C, Skoff RP, Lichtman AH, Wise LE, et al. (2013). Synaptic dysfunction in the hippocampus accompanies learning and memory deficits in human immunodeficiency virus type-1 Tat transgenic mice. Biol Psychiatry, 73:443-453.
Kim HJ, Martemyanov KA, Thayer SA (2008). Human immunodeficiency virus protein Tat induces synapse loss via a reversible process that is distinct from cell death. J Neurosci, 28:12604-12613.
Dickens AM, Yoo SW, Chin AC, Xu J, Johnson TP, Trout AL, et al. (2017). Chronic low-level expression of HIV-1 Tat promotes a neurodegenerative phenotype with aging. Sci Rep, 7:7748.
Xiao Y, Word B, Starlard-Davenport A, Haefele A, Lyn-Cook BD, Hammons G (2008). Age and gender affect DNMT3a and DNMT3b expression in human liver. Cell Biol Toxicol, 24:265-272.
Qian H, Xu X (2014). Reduction in DNA methyltransferases and alteration of DNA methylation pattern associate with mouse skin ageing. Exp Dermatol, 23:357-359.
Balada E, Ordi-Ros J, Serrano-Acedo S, Martinez-Lostao L, Rosa-Leyva M, Vilardell-Tarres M (2008). Transcript levels of DNA methyltransferases DNMT1, DNMT3A and DNMT3B in CD4+ T cells from patients with systemic lupus erythematosus. Immunology, 124:339-347.
Ciccarone F, Malavolta M, Calabrese R, Guastafierro T, Bacalini MG, Reale A, et al. (2016). Age-dependent expression of DNMT1 and DNMT3B in PBMCs from a large European population enrolled in the MARK-AGE study. Aging Cell, 15:755-765.
Pogribny IP, Vanyushin BF.2010. Age-related genomic hypomethylation. In Epigenetics of aging: Springer. 11-27.
Zampieri M, Ciccarone F, Calabrese R, Franceschi C, Burkle A, Caiafa P (2015). Reconfiguration of DNA methylation in aging. Mech Ageing Dev, 151:60-70.
Chow HM, Herrup K (2015). Genomic integrity and the ageing brain. Nat Rev Neurosci, 16:672-684.
Bogoi RN, de Pablo A, Valencia E, Martin-Carbonero L, Moreno V, Vilchez-Rueda HH, et al. (2018). Expression profiling of chromatin-modifying enzymes and global DNA methylation in CD4+ T cells from patients with chronic HIV infection at different HIV control and progression states. Clin Epigenetics, 10:20.
Periyasamy P, Thangaraj A, Guo ML, Hu G, Callen S, Buch S (2018). Epigenetic Promoter DNA Methylation of miR-124 Promotes HIV-1 Tat-Mediated Microglial Activation via MECP2-STAT3 Axis. J Neurosci, 38:5367-5383.
Yousefi P, Huen K, Dave V, Barcellos L, Eskenazi B, Holland N (2015). Sex differences in DNA methylation assessed by 450 K BeadChip in newborns. BMC Genomics, 16:911.
Hall E, Volkov P, Dayeh T, Esguerra JL, Salo S, Eliasson L, et al. (2014). Sex differences in the genome-wide DNA methylation pattern and impact on gene expression, microRNA levels and insulin secretion in human pancreatic islets. Genome Biol, 15:522.
Ceylan D, Scola G, Tunca Z, Isaacs-Trepanier C, Can G, Andreazza AC, et al. (2018). DNA redox modulations and global DNA methylation in bipolar disorder: Effects of sex, smoking and illness state. Psychiatry Res, 261:589-596.
Niedzwiecki MM, Liu X, Hall MN, Thomas T, Slavkovich V, Ilievski V, et al. (2015). Sex-specific associations of arsenic exposure with global DNA methylation and hydroxymethylation in leukocytes: results from two studies in Bangladesh. Cancer Epidemiol Biomarkers Prev, 24:1748-1757.
Gross AM, Jaeger PA, Kreisberg JF, Licon K, Jepsen KL, Khosroheidari M, et al. (2016). Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA. Mol Cell, 62:157-168.
Horvath S, Levine AJ (2015). HIV-1 Infection Accelerates Age According to the Epigenetic Clock. J Infect Dis, 212:1563-1573.