Journal of NeuroVirology

, Volume 25, Issue 5, pp 722–733 | Cite as

Astrocyte activation and altered metabolism in normal aging, age-related CNS diseases, and HAND

  • Bianca Cotto
  • Kalimuthusamy Natarajaseenivasan
  • Dianne LangfordEmail author


Astrocytes regulate local cerebral blood flow, maintain ion and neurotransmitter homeostasis, provide metabolic support, regulate synaptic activity, and respond to brain injury, insults, and infection. Because of their abundance, extensive connectivity, and multiple roles in the brain, astrocytes are intimately involved in normal functioning of the CNS and their dysregulation can lead to neuronal dysfunction. In normal aging, decreased biological functioning and reduced cognitive abilities are commonly experienced in individuals free of overt neurological disease. Moreover, in several age-related CNS diseases, chronic inflammation and altered metabolism have been reported. Since people with HIV (PWH) are reported to experience rapid aging with chronic inflammation, altered brain metabolism is likely to be exacerbated. In fact, many studies report altered metabolism in astrocytes in diseases such as Alzheimer’s, Parkinson’s, and HIV. This review will address the roles of astrocyte activation and altered metabolism in normal aging, in age-related CNS disease, and in HIV-associated neurocognitive disorders.


Astrocyte Metabolism HIV CNS Aging 



This work was supported by NIH P01 DA037830 to Kamel Khalili and Dianne Langford, NIH R01 MH107340 to Dianne Langford, NIH K99/R00 HL138268 to Santhanam Shanmughapriya, the Comprehensive NeuroAIDS Center to Kamel Khalili (NIH P30 MH09217), and Bianca Cotto was supported by T32MH079785.


  1. Abeti R, Abramov AY, Duchen MR (2011) Beta-amyloid activates PARP causing astrocytic metabolic failure and neuronal death. Brain 134:1658–1672PubMedCrossRefGoogle Scholar
  2. Abramov AY, Canevari L, Duchen MR (2004) Beta-amyloid peptides induce mitochondrial dysfunction and oxidative stress in astrocytes and death of neurons through activation of NADPH oxidase. J Neurosci 24:565–575PubMedPubMedCentralCrossRefGoogle Scholar
  3. Alberdi E, Wyssenbach A, Alberdi M, Sánchez-Gómez MV, Cavaliere F, Rodríguez JJ, Verkhratsky A, Matute C (2013) Ca(2+)-dependent endoplasmic reticulum stress correlates with astrogliosis in oligomeric amyloid β-treated astrocytes and in a model of Alzheimer’s disease. Aging Cell 12:292–302PubMedCrossRefGoogle Scholar
  4. Andersen AB, Law I, Krabbe KS, Bruunsgaard H, Ostrowski SR, Ullum H, Højgaard L, Lebech A, Gerstoft J, Kjaer A (2010) Cerebral FDG-PET scanning abnormalities in optimally treated HIV patients. J Neuroinflammation 7:13PubMedPubMedCentralCrossRefGoogle Scholar
  5. Atwood WJ, Tornatore CS, Meyers K, Major EO (1993) HIV-1 mRNA transcripts from persistently infected human fetal astrocytes. Ann N Y Acad Sci 693:324–325PubMedCrossRefGoogle Scholar
  6. Avdoshina V, Fields JA, Castellano P, Dedoni S, Palchik G, Trejo M, Adame A, Rockenstein E, Eugenin E, Masliah E, Mocchetti I (2016) The HIV protein gp120 alters mitochondrial dynamics in neurons. Neurotox Res 29:583–593PubMedPubMedCentralCrossRefGoogle Scholar
  7. Berchtold NC, Sabbagh MN, Beach TG, Kim RC, Cribbs DH, Cotman CW (2014) Brain gene expression patterns differentiate mild cognitive impairment from normal aged and Alzheimer’s disease. Neurobiol Aging 35:1961–1972PubMedPubMedCentralCrossRefGoogle Scholar
  8. Bero AW, Yan P, Roh JH, Cirrito JR, Stewart FR, Raichle ME, Lee JM, Holtzman DM (2011) Neuronal activity regulates the regional vulnerability to amyloid-β deposition. Nat Neurosci 14:750–756PubMedPubMedCentralCrossRefGoogle Scholar
  9. Bigl M, Brückner MK, Arendt T, Bigl V, Eschrich K (1999) Activities of key glycolytic enzymes in the brains of patients with Alzheimer’s disease. J Neural Transm (Vienna) 106:499–511CrossRefGoogle Scholar
  10. Boisvert MM, Erikson GA, Shokhirev MN, Allen NJ (2018) The aging astrocyte transcriptome from multiple regions of the mouse brain. Cell Rep 22:269–285PubMedPubMedCentralCrossRefGoogle Scholar
  11. Borgmann K, Ghorpade A (2018) Methamphetamine augments concurrent astrocyte mitochondrial stress, oxidative burden, and antioxidant capacity: tipping the balance in HIV-associated neurodegeneration. Neurotox Res 33:433–447PubMedCrossRefGoogle Scholar
  12. Borjabad A, Volsky DJ (2012) Common transcriptional signatures in brain tissue from patients with HIV-associated neurocognitive disorders, Alzheimer’s disease, and multiple sclerosis. J NeuroImmune Pharmacol 7:914–926PubMedPubMedCentralCrossRefGoogle Scholar
  13. Borjabad A, Brooks AI, Volsky DJ (2010) Gene expression profiles of HIV-1-infected glia and brain: toward better understanding of the role of astrocytes in HIV-1-associated neurocognitive disorders. J NeuroImmune Pharmacol 5:44–62PubMedCrossRefGoogle Scholar
  14. Boumezbeur F, Mason GF, de Graaf RA, Behar KL, Cline GW, Shulman GI, Rothman DL, Petersen KF (2010) Altered brain mitochondrial metabolism in healthy aging as assessed by in vivo magnetic resonance spectroscopy. J Cereb Blood Flow Metab 30:211–221PubMedCrossRefGoogle Scholar
  15. Brack-Werner R (1999) Astrocytes: HIV cellular reservoirs and important participants in neuropathogenesis. AIDS 13:1–22PubMedCrossRefGoogle Scholar
  16. Broe M, Kril J, Halliday GM (2004) Astrocytic degeneration relates to the severity of disease in frontotemporal dementia. Brain 127:2214–2220PubMedCrossRefGoogle Scholar
  17. Brooks WM, Lynch PJ, Ingle CC, Hatton A, Emson PC, Faull RL, Starkey MP (2007) Gene expression profiles of metabolic enzyme transcripts in Alzheimer’s disease. Brain Res 1127:127–135PubMedCrossRefGoogle Scholar
  18. Cahoy JD, Emery B, Kaushal A, Foo LC, Zamanian JL, Christopherson KS, Xing Y, Lubischer JL, Krieg PA, Krupenko SA, Thompson WJ, Barres BA (2008) A transcriptome database for astrocytes, neurons, and oligodendrocytes: a new resource for understanding brain development and function. J Neurosci 28:264–278PubMedPubMedCentralCrossRefGoogle Scholar
  19. Cai Z, Wan CQ, Liu Z (2017) Astrocyte and Alzheimer’s disease. J Neurol 264:2068–2074PubMedCrossRefGoogle Scholar
  20. Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzalez B (2009) Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury-induced cytokine response after excitotoxic damage. J Neurosci Res 87:2484–2497PubMedCrossRefGoogle Scholar
  21. Carter SF, Schöll M, Almkvist O, Wall A, Engler H, Långström B, Nordberg A (2012) Evidence for astrocytosis in prodromal Alzheimer disease provided by 11C-deuterium-L-deprenyl: a multitracer PET paradigm combining 11C-Pittsburgh compound B and 18F-FDG. J Nucl Med 53:37–46PubMedCrossRefGoogle Scholar
  22. Cassol E, Misra V, Dutta A, Morgello S, Gabuzda D (2014) Cerebrospinal fluid metabolomics reveals altered waste clearance and accelerated aging in HIV patients with neurocognitive impairment. AIDS 28:1579–1591PubMedPubMedCentralCrossRefGoogle Scholar
  23. Clarke LE, Liddelow SA, Chakraborty C, Münch AE, Heiman M, Barres BA (2018) Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci U S A 115:E1896–E1905PubMedPubMedCentralCrossRefGoogle Scholar
  24. Cohen RA, Seider TR, Navia B (2015) HIV effects on age-associated neurocognitive dysfunction: premature cognitive aging or neurodegenerative disease? Alzheimers Res Ther 7:37PubMedPubMedCentralCrossRefGoogle Scholar
  25. Cole JH, Underwood J, Caan MW, De Francesco D, van Zoest RA, Leech R, Wit FW, Portegies P, Geurtsen GJ, Schmand BA, Schim van der Loeff MF, Franceschi C, Sabin CA, Majoie CB, Winston A, Reiss P, Sharp DJ, collaboration C (2017) Increased brain-predicted aging in treated HIV disease. Neurology 88:1349–1357PubMedPubMedCentralCrossRefGoogle Scholar
  26. Cunnane SC, Courchesne-Loyer A, St-Pierre V, Vandenberghe C, Pierotti T, Fortier M, Croteau E, Castellano CA (2016) Can ketones compensate for deteriorating brain glucose uptake during aging? Implications for the risk and treatment of Alzheimer’s disease. Ann N Y Acad Sci 1367:12–20PubMedCrossRefGoogle Scholar
  27. De Santi S, de Leon MJ, Rusinek H, Convit A, Tarshish CY, Roche A, Tsui WH, Kandil E, Boppana M, Daisley K, Wang GJ, Schlyer D, Fowler J (2001) Hippocampal formation glucose metabolism and volume losses in MCI and AD. Neurobiol Aging 22:529–539PubMedCrossRefGoogle Scholar
  28. De Simone FI, Darbinian N, Amini S, Muniswamy M, White MK, Elrod JW, Datta PK, Langford D, Khalili K (2016) HIV-1 Tat and cocaine impair survival of cultured primary neuronal cells via a mitochondrial pathway. J NeuroImmune Pharmacol 11:358–368PubMedPubMedCentralCrossRefGoogle Scholar
  29. De Strooper B, Karran E (2016) The cellular phase of Alzheimer’s disease. Cell 164:603–615PubMedCrossRefGoogle Scholar
  30. Desplats P, Dumaop W, Smith D, Adame A, Everall I, Letendre S, Ellis R, Cherner M, Grant I, Masliah E (2013) Molecular and pathologic insights from latent HIV-1 infection in the human brain. Neurology 80:1415–1423PubMedPubMedCentralCrossRefGoogle Scholar
  31. Dickens AM, Anthony DC, Deutsch R, Mielke MM, Claridge TD, Grant I, Franklin D, Rosario D, Marcotte T, Letendre S, McArthur JC, Haughey NJ (2015) Cerebrospinal fluid metabolomics implicate bioenergetic adaptation as a neural mechanism regulating shifts in cognitive states of HIV-infected patients. AIDS 29:559–569PubMedPubMedCentralGoogle Scholar
  32. Doyle JP, Dougherty JD, Heiman M, Schmidt EF, Stevens TR, Ma G, Bupp S, Shrestha P, Shah RD, Doughty ML, Gong S, Greengard P, Heintz N (2008) Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell 135:749–762PubMedPubMedCentralCrossRefGoogle Scholar
  33. Duara R, Grady C, Haxby J, Sundaram M, Cutler NR, Heston L, Moore A, Schlageter N, Larson S, Rapoport SI (1986) Positron emission tomography in Alzheimer’s disease. Neurology 36:879–887PubMedCrossRefGoogle Scholar
  34. Dufour CA, Marquine MJ, Fazeli PL, Henry BL, Ellis RJ, Grant I, Moore DJ, Group H (2013) Physical exercise is associated with less neurocognitive impairment among HIV-infected adults. J Neuro-Oncol 19:410–417Google Scholar
  35. Dumas JA (2015) What is normal cognitive aging? Evidence from task-based functional neuroimaging. Curr Behav Neurosci Rep 2:256–261PubMedPubMedCentralCrossRefGoogle Scholar
  36. Ebert D, Haller RG, Walton ME (2003) Energy contribution of octanoate to intact rat brain metabolism measured by 13C nuclear magnetic resonance spectroscopy. J Neurosci 23:5928–5935PubMedPubMedCentralCrossRefGoogle Scholar
  37. Edén A, Price RW, Spudich S, Fuchs D, Hagberg L, Gisslén M (2007) Immune activation of the central nervous system is still present after >4 years of effective highly active antiretroviral therapy. J Infect Dis 196:1779–1783PubMedCrossRefGoogle Scholar
  38. Emirandetti A, Graciele Zanon R, Sabha M, de Oliveira AL (2006) Astrocyte reactivity influences the number of presynaptic terminals apposed to spinal motoneurons after axotomy. Brain Res 1095:35–42PubMedCrossRefGoogle Scholar
  39. Emsley JG, Macklis JD (2006) Astroglial heterogeneity closely reflects the neuronal-defined anatomy of the adult murine CNS. Neuron Glia Biol 2:175–186PubMedPubMedCentralCrossRefGoogle Scholar
  40. Ensoli B, Buonaguro L, Barillari G, Fiorelli V, Gendelman R, Morgan RA, Wingfield P, Gallo RC (1993) Release, uptake, and effects of extracellular human immunodeficiency virus type 1 Tat protein on cell growth and viral transactivation. J Virol 67:277–287PubMedPubMedCentralGoogle Scholar
  41. Ferrer I (2017) Diversity of astroglial responses across human neurodegenerative disorders and brain aging. Brain Pathol 27:645–674PubMedCrossRefGoogle Scholar
  42. Fitting S, Knapp PE, Zou S, Marks WD, Bowers MS, Akbarali HI, Hauser KF (2014) Interactive HIV-1 Tat and morphine-induced synaptodendritic injury is triggered through focal disruptions in Na+ influx, mitochondrial instability, and Ca2+ overload. J Neurosci 34:12850–12864PubMedPubMedCentralCrossRefGoogle Scholar
  43. Fjell AM, McEvoy L, Holland D, Dale AM, Walhovd KB, Initiative ADN (2014) What is normal in normal aging? Effects of aging, amyloid and Alzheimer’s disease on the cerebral cortex and the hippocampus. Prog Neurobiol 117:20–40PubMedPubMedCentralCrossRefGoogle Scholar
  44. Förster S, Grimmer T, Miederer I, Henriksen G, Yousefi BH, Graner P, Wester HJ, Förstl H, Kurz A, Dickerson BC, Bartenstein P, Drzezga A (2012) Regional expansion of hypometabolism in Alzheimer’s disease follows amyloid deposition with temporal delay. Biol Psychiatry 71:792–797PubMedCrossRefGoogle Scholar
  45. Franceschi C, Capri M, Monti D, Giunta S, Olivieri F, Sevini F, Panourgia MP, Invidia L, Celani L, Scurti M, Cevenini E, Castellani GC, Salvioli S (2007) Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans. Mech Ageing Dev 128:92–105PubMedCrossRefGoogle Scholar
  46. Fu W, Shi D, Westaway D, Jhamandas JH (2015) Bioenergetic mechanisms in astrocytes may contribute to amyloid plaque deposition and toxicity. J Biol Chem 290:12504–12513PubMedPubMedCentralCrossRefGoogle Scholar
  47. Garwood CJ, Pooler AM, Atherton J, Hanger DP, Noble W (2011) Astrocytes are important mediators of Aβ-induced neurotoxicity and tau phosphorylation in primary culture. Cell Death Dis 2:e167PubMedPubMedCentralCrossRefGoogle Scholar
  48. Gulyás B, Pavlova E, Kása P, Gulya K, Bakota L, Várszegi S, Keller E, Horváth MC, Nag S, Hermecz I, Magyar K, Halldin C (2011) Activated MAO-B in the brain of Alzheimer patients, demonstrated by [11C]-L-deprenyl using whole hemisphere autoradiography. Neurochem Int 58:60–68PubMedCrossRefGoogle Scholar
  49. Halim ND, Mcfate T, Mohyeldin A, Okagaki P, Korotchkina LG, Patel MS, Jeoung NH, Harris RA, Schell MJ, Verma A (2010) Phosphorylation status of pyruvate dehydrogenase distinguishes metabolic phenotypes of cultured rat brain astrocytes and neurons. Glia 58:1168–1176PubMedPubMedCentralCrossRefGoogle Scholar
  50. Harezlak J, Buchthal S, Taylor M, Schifitto G, Zhong J, Daar E, Alger J, Singer E, Campbell T, Yiannoutsos C, Cohen R, Navia B, Consortium HN (2011) Persistence of HIV-associated cognitive impairment, inflammation, and neuronal injury in era of highly active antiretroviral treatment. AIDS 25:625–633PubMedPubMedCentralCrossRefGoogle Scholar
  51. Harris JL, Yeh HW, Swerdlow RH, Choi IY, Lee P, Brooks WM (2014) High-field proton magnetic resonance spectroscopy reveals metabolic effects of normal brain aging. Neurobiol Aging 35:1686–1694PubMedPubMedCentralCrossRefGoogle Scholar
  52. Harris JL, Choi IY, Brooks WM (2015) Probing astrocyte metabolism in vivo: proton magnetic resonance spectroscopy in the injured and aging brain. Front Aging Neurosci 7:202PubMedPubMedCentralGoogle Scholar
  53. Heaton RK, Clifford DB, Franklin DR, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL, Marcotte TD, Atkinson JH, Rivera-Mindt M, Vigil OR, Taylor MJ, Collier AC, Marra CM, Gelman BB, McArthur JC, Morgello S, Simpson DM, McCutchan JA, Abramson I, Gamst A, Fennema-Notestine C, Jernigan TL, Wong J, Grant I, Group C (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER study. Neurology 75:2087–2096PubMedPubMedCentralCrossRefGoogle Scholar
  54. Hoppe JB, Rattray M, Tu H, Salbego CG, Cimarosti H (2013) SUMO-1 conjugation blocks beta-amyloid-induced astrocyte reactivity. Neurosci Lett 546:51–56PubMedCrossRefGoogle Scholar
  55. Hou L, Liu Y, Wang X, Ma H, He J, Zhang Y, Yu C, Guan W, Ma Y (2011) The effects of amyloid-β42 oligomer on the proliferation and activation of astrocytes in vitro. In Vitro Cell Dev Biol Anim 47:573–580PubMedCrossRefGoogle Scholar
  56. Hui L, Chen X, Bhatt D, Geiger NH, Rosenberger TA, Haughey NJ, Masino SA, Geiger JD (2012) Ketone bodies protection against HIV-1 Tat-induced neurotoxicity. J Neurochem 122:382–391PubMedPubMedCentralCrossRefGoogle Scholar
  57. Ibáñez V, Pietrini P, Alexander GE, Furey ML, Teichberg D, Rajapakse JC, Rapoport SI, Schapiro MB, Horwitz B (1998) Regional glucose metabolic abnormalities are not the result of atrophy in Alzheimer’s disease. Neurology 50:1585–1593PubMedCrossRefGoogle Scholar
  58. Ingelsson M, Fukumoto H, Newell KL, Growdon JH, Hedley-Whyte ET, Frosch MP, Albert MS, Hyman BT, Irizarry MC (2004) Early Abeta accumulation and progressive synaptic loss, gliosis, and tangle formation in AD brain. Neurology 62:925–931PubMedCrossRefGoogle Scholar
  59. Jana A, Pahan K (2010) Fibrillar amyloid-beta-activated human astroglia kill primary human neurons via neutral sphingomyelinase: implications for Alzheimer’s disease. J Neurosci 30:12676–12689PubMedPubMedCentralCrossRefGoogle Scholar
  60. Jiang T, Cadenas E (2014) Astrocytic metabolic and inflammatory changes as a function of age. Aging Cell 13:1059–1067PubMedPubMedCentralCrossRefGoogle Scholar
  61. John Lin CC, Yu K, Hatcher A, Huang TW, Lee HK, Carlson J, Weston MC, Chen F, Zhang Y, Zhu W, Mohila CA, Ahmed N, Patel AJ, Arenkiel BR, Noebels JL, Creighton CJ, Deneen B (2017) Identification of diverse astrocyte populations and their malignant analogs. Nat Neurosci 20:396–405PubMedCrossRefGoogle Scholar
  62. Kadish I, Thibault O, Blalock EM, Chen KC, Gant JC, Porter NM, Landfield PW (2009) Hippocampal and cognitive aging across the lifespan: a bioenergetic shift precedes and increased cholesterol trafficking parallels memory impairment. J Neurosci 29:1805–1816PubMedPubMedCentralCrossRefGoogle Scholar
  63. Kalpouzos G, Chételat G, Baron JC, Landeau B, Mevel K, Godeau C, Barré L, Constans JM, Viader F, Eustache F, Desgranges B (2009) Voxel-based mapping of brain gray matter volume and glucose metabolism profiles in normal aging. Neurobiol Aging 30:112–124PubMedCrossRefGoogle Scholar
  64. 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 162:1693–1707PubMedPubMedCentralCrossRefGoogle Scholar
  65. Kitayama H, Miura Y, Ando Y, Hoshino S, Ishizaka Y, Koyanagi Y (2008) Human immunodeficiency virus type 1 Vpr inhibits axonal outgrowth through induction of mitochondrial dysfunction. J Virol 82:2528–2542PubMedCrossRefGoogle Scholar
  66. Lana D, Iovino L, Nosi D, Wenk GL, Giovannini MG (2016) The neuron-astrocyte-microglia triad involvement in neuroinflammaging mechanisms in the CA3 hippocampus of memory-impaired aged rats. Exp Gerontol 83:71–88PubMedCrossRefGoogle Scholar
  67. Laranjeira A, Schulz J, Dotti CG (2016) Genes related to fatty acid β-oxidation play a role in the functional decline of the Drosophila brain with age. PLoS One 11:e0161143PubMedPubMedCentralCrossRefGoogle Scholar
  68. Lee CK, Weindruch R, Prolla TA (2000) Gene-expression profile of the ageing brain in mice. Nat Genet 25:294–297PubMedCrossRefGoogle Scholar
  69. Levine AJ, Miller JA, Shapshak P, Gelman B, Singer EJ, Hinkin CH, Commins D, Morgello S, Grant I, Horvath S (2013) Systems analysis of human brain gene expression: mechanisms for HIV-associated neurocognitive impairment and common pathways with Alzheimer’s disease. BMC Med Genet 6:4Google Scholar
  70. Levine AJ, Quach A, Moore DJ, Achim CL, Soontornniyomkij V, Masliah E, Singer EJ, Gelman B, Nemanim N, Horvath S (2016) Accelerated epigenetic aging in brain is associated with pre-mortem HIV-associated neurocognitive disorders. J Neuro-Oncol 22:366–375Google Scholar
  71. Liang WS, Reiman EM, Valla J, Dunckley T, Beach TG, Grover A, Niedzielko TL, Schneider LE, Mastroeni D, Caselli R, Kukull W, Morris JC, Hulette CM, Schmechel D, Rogers J, Stephan DA (2008) Alzheimer’s disease is associated with reduced expression of energy metabolism genes in posterior cingulate neurons. Proc Natl Acad Sci U S A 105:4441–4446PubMedPubMedCentralCrossRefGoogle Scholar
  72. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE, Chung WS, Peterson TC, Wilton DK, Frouin A, Napier BA, Panicker N, Kumar M, Buckwalter MS, Rowitch DH, Dawson VL, Dawson TM, Stevens B, Barres BA (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487PubMedPubMedCentralCrossRefGoogle Scholar
  73. Lindenberger U (2014) Human cognitive aging: corriger la fortune? Science 346:572–578PubMedCrossRefGoogle Scholar
  74. Lynch AM, Murphy KJ, Deighan BF, O'Reilly JA, Gun'ko YK, Cowley TR, Gonzalez-Reyes RE, Lynch MA (2010) The impact of glial activation in the aging brain. Aging Dis 1:262–278PubMedPubMedCentralGoogle Scholar
  75. Maher FO, Martin DS, Lynch MA (2004) Increased IL-1beta in cortex of aged rats is accompanied by downregulation of ERK and PI-3 kinase. Neurobiol Aging 25:795–806PubMedCrossRefGoogle Scholar
  76. Mamik MK, Asahchop EL, Chan WF, Zhu Y, Branton WG, McKenzie BA, Cohen EA, Power C (2016) Insulin treatment prevents neuroinflammation and neuronal injury with restored neurobehavioral function in models of HIV/AIDS neurodegeneration. J Neurosci 36:10683–10695PubMedPubMedCentralCrossRefGoogle Scholar
  77. Masliah E, Ge N, Mucke L (1996) Pathogenesis of HIV-1 associated neurodegeneration. Crit Rev Neurobiol 10:57–67PubMedCrossRefGoogle Scholar
  78. Mateen FJ, Shinohara RT, Carone M, Miller EN, McArthur JC, Jacobson LP, Sacktor N, Investigators MACSM (2012) Neurologic disorders incidence in HIV+ vs HIV- men: multicenter AIDS cohort study, 1996-2011. Neurology 79:1873–1880PubMedPubMedCentralCrossRefGoogle Scholar
  79. Middeldorp J, Hol EM (2011) GFAP in health and disease. Prog Neurobiol 93:421–443PubMedCrossRefGoogle Scholar
  80. Miller RH, Raff MC (1984) Fibrous and protoplasmic astrocytes are biochemically and developmentally distinct. J Neurosci 4:585–592PubMedPubMedCentralCrossRefGoogle Scholar
  81. Minagar A, Shapshak P, Fujimura R, Ownby R, Heyes M, Eisdorfer C (2002) The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 202:13–23PubMedCrossRefPubMedCentralGoogle Scholar
  82. Morgan TE, Xie Z, Goldsmith S, Yoshida T, Lanzrein AS, Stone D, Rozovsky I, Perry G, Smith MA, Finch CE (1999) The mosaic of brain glial hyperactivity during normal ageing and its attenuation by food restriction. Neuroscience 89:687–699PubMedCrossRefGoogle Scholar
  83. Mosconi L, Mistur R, Switalski R, Tsui WH, Glodzik L, Li Y, Pirraglia E, De Santi S, Reisberg B, Wisniewski T, de Leon MJ (2009) FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease. Eur J Nucl Med Mol Imaging 36:811–822PubMedPubMedCentralCrossRefGoogle Scholar
  84. Nagele RG, D'Andrea MR, Lee H, Venkataraman V, Wang HY (2003) Astrocytes accumulate A beta 42 and give rise to astrocytic amyloid plaques in Alzheimer disease brains. Brain Res 971:197–209PubMedCrossRefGoogle Scholar
  85. Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer’s disease. Neurobiol Aging 25:663–674PubMedCrossRefGoogle Scholar
  86. Natarajaseenivasan K, Cotto B, Shanmughapriya S, Lombardi AA, Datta PK, Madesh M, Elrod JW, Khalili K, Langford D (2018) Astrocytic metabolic switch is a novel etiology for cocaine and HIV-1 Tat-mediated neurotoxicity. Cell Death Dis 9:415PubMedPubMedCentralCrossRefGoogle Scholar
  87. Nichols NR, Day JR, Laping NJ, Johnson SA, Finch CE (1993) GFAP mRNA increases with age in rat and human brain. Neurobiol Aging 14:421–429PubMedCrossRefGoogle Scholar
  88. Nilsen LH, Witter MP, Sonnewald U (2014) Neuronal and astrocytic metabolism in a transgenic rat model of Alzheimer’s disease. J Cereb Blood Flow Metab 34:906–914PubMedPubMedCentralCrossRefGoogle Scholar
  89. Nolan Y, Maher FO, Martin DS, Clarke RM, Brady MT, Bolton AE, Mills KH, Lynch MA (2005) Role of interleukin-4 in regulation of age-related inflammatory changes in the hippocampus. J Biol Chem 280:9354–9362PubMedCrossRefGoogle Scholar
  90. 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 178:869–876PubMedCrossRefGoogle Scholar
  91. Oberheim NA, Wang X, Goldman S, Nedergaard M (2006) Astrocytic complexity distinguishes the human brain. Trends Neurosci 29:547–553PubMedCrossRefGoogle Scholar
  92. Oh H, Madison C, Baker S, Rabinovici G, Jagust W (2016) Dynamic relationships between age, amyloid-β deposition, and glucose metabolism link to the regional vulnerability to Alzheimer’s disease. Brain 139:2275–2289PubMedPubMedCentralCrossRefGoogle Scholar
  93. Panov A, Orynbayeva Z, Vavilin V, Lyakhovich V (2014) Fatty acids in energy metabolism of the central nervous system. Biomed Res Int 2014:472459PubMedPubMedCentralCrossRefGoogle Scholar
  94. Pfefferbaum A, Rogosa DA, Rosenbloom MJ, Chu W, Sassoon SA, Kemper CA, Deresinski S, Rohlfing T, Zahr NM, Sullivan EV (2014) Accelerated aging of selective brain structures in human immunodeficiency virus infection: a controlled, longitudinal magnetic resonance imaging study. Neurobiol Aging 35:1755–1768PubMedPubMedCentralCrossRefGoogle Scholar
  95. Porchet R, Probst A, Bouras C, Dráberová E, Dráber P, Riederer BM (2003) Analysis of glial acidic fibrillary protein in the human entorhinal cortex during aging and in Alzheimer’s disease. Proteomics 3:1476–1485PubMedCrossRefGoogle Scholar
  96. Ranki A, Nyberg M, Ovod V, Haltia M, Elovaara I, Raininko R, Haapasalo H, Krohn K (1995) Abundant expression of HIV Nef and Rev proteins in brain astrocytes in vivo is associated with dementia. AIDS 9:1001–1008PubMedCrossRefGoogle Scholar
  97. Raz N, Rodrigue KM (2006) Differential aging of the brain: patterns, cognitive correlates and modifiers. Neurosci Biobehav Rev 30:730–748PubMedPubMedCentralCrossRefGoogle Scholar
  98. Rodríguez JJ, Olabarria M, Chvatal A, Verkhratsky A (2009) Astroglia in dementia and Alzheimer’s disease. Cell Death Differ 16:378–385PubMedCrossRefGoogle Scholar
  99. Rodríguez 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 35:15–23PubMedCrossRefGoogle Scholar
  100. Rodríguez-Arellano JJ, Parpura V, Zorec R, Verkhratsky A (2016) Astrocytes in physiological aging and Alzheimer’s disease. Neuroscience 323:170–182PubMedCrossRefGoogle Scholar
  101. Rozzi SJ, Avdoshina V, Fields JA, Trejo M, Ton HT, Ahern GP, Mocchetti I (2017) Human immunodeficiency virus promotes mitochondrial toxicity. Neurotox Res 32:723–733PubMedPubMedCentralCrossRefGoogle Scholar
  102. Ru W, Tang SJ (2017) HIV-associated synaptic degeneration. Mol Brain 10:40PubMedPubMedCentralCrossRefGoogle Scholar
  103. Sabri F, Titanji K, De Milito A, Chiodi F (2003) Astrocyte activation and apoptosis: their roles in the neuropathology of HIV infection. Brain Pathol 13:84–94PubMedCrossRefGoogle Scholar
  104. Saura J, Luque JM, Cesura AM, Da Prada M, Chan-Palay V, Huber G, Löffler J, Richards JG (1994) Increased monoamine oxidase B activity in plaque-associated astrocytes of Alzheimer brains revealed by quantitative enzyme radioautography. Neuroscience 62:15–30PubMedCrossRefGoogle Scholar
  105. Scuderi C, Stecca C, Iacomino A, Steardo L (2013) Role of astrocytes in major neurological disorders: the evidence and implications. IUBMB Life 65:957–961PubMedCrossRefGoogle Scholar
  106. Serramía MJ, Muñoz-Fernández M, Álvarez S (2015) HIV-1 increases TLR responses in human primary astrocytes. Sci Rep 5:17887PubMedPubMedCentralCrossRefGoogle Scholar
  107. Serrano-Pozo A, Mielke ML, Gómez-Isla T, Betensky RA, Growdon JH, Frosch MP, Hyman BT (2011) Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease. Am J Pathol 179:1373–1384PubMedPubMedCentralCrossRefGoogle Scholar
  108. Shah A, Kumar A (2016) HIV-1 gp120-mediated mitochondrial dysfunction and HIV-associated neurological disorders. Neurotox Res 30:135–137PubMedCrossRefGoogle Scholar
  109. van Sighem AI, Gras LA, Reiss P, Brinkman K, de Wolf F, study Anoc (2010) Life expectancy of recently diagnosed asymptomatic HIV-infected patients approaches that of uninfected individuals. AIDS 24:1527–1535PubMedCrossRefGoogle Scholar
  110. Sofroniew MV, Vinters HV (2010) Astrocytes: biology and pathology. Acta Neuropathol 119:7–35PubMedPubMedCentralCrossRefGoogle Scholar
  111. Soreq L, Rose J, Soreq E, Hardy J, Trabzuni D, Cookson MR, Smith C, Ryten M, Patani R, Ule J, Consortium UBE, Consortium NABE (2017) Major shifts in glial regional identity are a transcriptional hallmark of human brain aging. Cell Rep 18:557–570PubMedPubMedCentralCrossRefGoogle Scholar
  112. Souza DG, Bellaver B, Raupp GS, Souza DO, Quincozes-Santos A (2015) Astrocytes from adult Wistar rats aged in vitro show changes in glial functions. Neurochem Int 90:93–97PubMedCrossRefGoogle Scholar
  113. Stafstrom CE, Rho JM (2012) The ketogenic diet as a treatment paradigm for diverse neurological disorders. Front Pharmacol 3:59PubMedPubMedCentralCrossRefGoogle Scholar
  114. Stevens PR, Gawryluk JW, Hui L, Chen X, Geiger JD (2014) Creatine protects against mitochondrial dysfunction associated with HIV-1 Tat-induced neuronal injury. Curr HIV Res 12:378–387PubMedCrossRefGoogle Scholar
  115. Teodorof-Diedrich C, Spector SA (2018) Human immunodeficiency virus type 1 gp120 and Tat induce mitochondrial fragmentation and incomplete mitophagy in human neurons. J Virol 92:e00993-18Google Scholar
  116. Terao A, Apte-Deshpande A, Dousman L, Morairty S, Eynon BP, Kilduff TS, Freund YR (2002) Immune response gene expression increases in the aging murine hippocampus. J Neuroimmunol 132:99–112PubMedCrossRefGoogle Scholar
  117. Toggas SM, Masliah E, Rockenstein EM, Rall GF, Abraham CR, Mucke L (1994) Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice. Nature 367:188–193PubMedCrossRefGoogle Scholar
  118. Towgood KJ, Pitkanen M, Kulasegaram R, Fradera A, Soni S, Sibtain N, Reed LJ, Bradbeer C, Barker GJ, Dunn JT, Zelaya F, Kopelman MD (2013) Regional cerebral blood flow and FDG uptake in asymptomatic HIV-1 men. Hum Brain Mapp 34:2484–2493PubMedCrossRefGoogle Scholar
  119. Tyor WR, Power C, Gendelman HE, Markham RB (1993) A model of human immunodeficiency virus encephalitis in scid mice. Proc Natl Acad Sci U S A 90:8658–8662PubMedPubMedCentralCrossRefGoogle Scholar
  120. Verhaeghen P, Cerella J (2002) Aging, executive control, and attention: a review of meta-analyses. Neurosci Biobehav Rev 26:849–857PubMedCrossRefGoogle Scholar
  121. Villeneuve LM, Purnell PR, Stauch KL, Callen SE, Buch SJ, Fox HS (2016) HIV-1 transgenic rats display mitochondrial abnormalities consistent with abnormal energy generation and distribution. J Neuro-Oncol 22:564–574Google Scholar
  122. Vitkovic L, da Cunha A (1995) Role for astrocytosis in HIV-1-associated dementia. Curr Top Microbiol Immunol 202:105–116PubMedGoogle Scholar
  123. Wang Y, Santerre M, Tempera I, Martin K, Mukerjee R, Sawaya BE (2017) HIV-1 Vpr disrupts mitochondria axonal transport and accelerates neuronal aging. Neuropharmacology 117:364–375PubMedPubMedCentralCrossRefGoogle Scholar
  124. Weber M, Wu T, Hanson JE et al (2015) Cognitive deficits, changes in synaptic function, and brain pathology in a mouse model of normal aging (1,2,3). eNeuro 2(5):ENEURO.0047-15Google Scholar
  125. Yamazaki D, Horiuchi J, Ueno K, Ueno T, Saeki S, Matsuno M, Naganos S, Miyashita T, Hirano Y, Nishikawa H, Taoka M, Yamauchi Y, Isobe T, Honda Y, Kodama T, Masuda T, Saitoe M (2014) Glial dysfunction causes age-related memory impairment in Drosophila. Neuron 84:753–763PubMedCrossRefGoogle Scholar
  126. Yang Y, Yao H, Lu Y, Wang C, Buch S (2010) Cocaine potentiates astrocyte toxicity mediated by human immunodeficiency virus (HIV-1) protein gp120. PLoS One 5:e13427PubMedPubMedCentralCrossRefGoogle Scholar
  127. Yang L, Yao H, Chen X, Cai Y, Callen S, Buch S (2016) Role of sigma receptor in cocaine-mediated induction of glial fibrillary acidic protein: implications for HAND. Mol Neurobiol 53:1329–1342PubMedCrossRefGoogle Scholar
  128. Yao J, Rettberg JR, Klosinski LP, Cadenas E, Brinton RD (2011) Shift in brain metabolism in late onset Alzheimer’s disease: implications for biomarkers and therapeutic interventions. Mol Asp Med 32:247–257CrossRefGoogle Scholar
  129. Yao Y, Huang JZ, Chen Y, Hu HJ, Tang X, Li X (2018) Effects and mechanism of amyloid β1-42 on mitochondria in astrocytes. Mol Med Rep 17:6997–7004PubMedPubMedCentralGoogle Scholar
  130. Yeh TH, Lee DY, Gianino SM, Gutmann DH (2009) Microarray analyses reveal regional astrocyte heterogeneity with implications for neurofibromatosis type 1 (NF1)-regulated glial proliferation. Glia 57:1239–1249PubMedPubMedCentralCrossRefGoogle Scholar
  131. Yoshida T, Goldsmith SK, Morgan TE, Stone DJ, Finch CE (1996) Transcription supports age-related increases of GFAP gene expression in the male rat brain. Neurosci Lett 215:107–110PubMedCrossRefGoogle Scholar
  132. Young AC, Yiannoutsos CT, Hegde M, Lee E, Peterson J, Walter R, Price RW, Meyerhoff DJ, Spudich S (2014) Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection. Neurology 83:1592–1600PubMedPubMedCentralCrossRefGoogle Scholar
  133. Zhang Y, Barres BA (2010) Astrocyte heterogeneity: an underappreciated topic in neurobiology. Curr Opin Neurobiol 20:588–594PubMedCrossRefGoogle Scholar
  134. Zhang X, Wu J, Liu H (2013) Age- and gender-related metabonomic alterations in striatum and cerebellar cortex in rats. Brain Res 1507:28–34PubMedCrossRefGoogle Scholar
  135. 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 27:296–305PubMedCrossRefGoogle Scholar
  136. Zhou L, Diefenbach E, Crossett B, Tran SL, Ng T, Rizos H, Rua R, Wang B, Kapur A, Gandhi K, Brew BJ, Saksena NK (2010) 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. Mol Neurodegener 5:27PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Journal of NeuroVirology, Inc. 2019

Authors and Affiliations

  1. 1.Department of Neuroscience and Center for NeurovirologyLewis Katz School of Medicine at Temple UniversityPhiladelphiaUSA

Personalised recommendations