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Increased frequency of α-synuclein in the substantia nigra in human immunodeficiency virus infection

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Abstract

The frequency of neurodegenerative markers among long surviving human immunodeficiency virus (HIV)-infected individuals is unknown, therefore, the present study investigated the frequency of α-synuclein, β-amyloid, and HIV-associated brain pathology in the brains of older HIV-infected individuals. We examined the substantia nigra of 73 clinically well-characterized HIV-infected individuals aged 50 to 76 years from the National NeuroAIDS Tissue Consortium. We also examined the frontal and temporal cortical regions of a subset of 36 individuals. Neuritic α-synuclein expression was found in 16% (12/73) of the substantia nigra of the HIV+cases and none of the older control cases (0/18). β-Amyloid deposits were prevalent and found in nearly all of the HIV+ cases (35/36). Despite these increases of degenerative pathology, HIV-associated brain pathology was present in only 10% of cases. Among older HIV+adults, HIV-associated brain pathology does not appear elevated; however, the frequency of both α-synuclein and β-amyloid is higher than that found in older healthy persons. The increased prevalence of α-synuclein and β-amyloid in the brains of older HIV-infected individuals may predict an increased risk of developing neurodegenerative disease.

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References

  • An SF, Giometto B, Groves M, Miller RF, Beckett AA, Gray F, Tavolato B, Scaravilli F (1997). Axonal damage revealed by accumulation of beta-APP in HIV-positive individuals without AIDS. J Neuropathol Exp Neurol 56: 1262–1268.

    Article  CAS  PubMed  Google Scholar 

  • Anthony IC, Ramage SN, Carnie FW, Simmonds P, Bell JE (2006). Accelerated tau deposition in the brains of individuals infected with human immunodeficiency virus-1 before and after the advent of highly active antiretroviral therapy. Acta Neuropathol 111: 529–538.

    Article  CAS  PubMed  Google Scholar 

  • Apcher GS, Heink S, Zantopf D, Kloetzel PM, Schmid HP, Mayer RJ, Kruger E (2003). Human immunodeficiency virus-1 Tat protein interacts with distinct proteasomal alpha and beta subunits. FEBS Lett 553: 200–204.

    Article  CAS  PubMed  Google Scholar 

  • Baba M, Nakajo S, Tu PH, Tomita T, Nakaya K, Lee VM, Trojanowski JQ, Iwatsubo T (1998). Aggregation of alpha-synuclein in Lewy bodies of sporadic Parkinson’s disease and dementia with Lewy bodies. Am J Pathol 152: 879–884.

    CAS  PubMed  Google Scholar 

  • Bell JE, Brettle RP, Chiswick A, Simmonds P (1998). HIV encephalitis, proviral load and dementia in drug users and homosexuals with AIDS Effect of neocortical involvement. Brain 121: 2043–2052.

    Article  PubMed  Google Scholar 

  • Braak H, Rub U, Sandmann-Keil D, Gai WP, de Vos RA, Jansen Steur EN, Arai K, Braak E (2000). Parkinson’s disease: affection of brain stem nuclei controlling premotor and motor neurons of the somatomotor system. Acta Neuropathol (Berl) 99: 489–495.

    Article  CAS  Google Scholar 

  • Budka H, Wiley CA, Kleihues R, Artigas J, Asbury AK, Cho ES, Cornblath DR, Dal Canto MC, DeGirolami U, Dickson D, et al (1991). HIV∢ssociated disease of the nervous system: review of nomenclature and proposal for neuropathology-based terminology. Brain Pathol 1: 143–152.

    Article  CAS  PubMed  Google Scholar 

  • Cabin DE, Shimazu K, Murphy D, Cole NB, Gottschalk W, McIlwain KL, Orrison B, Chen A, Ellis CE, Paylor R, Lu B, Nussbaum RL (2002). Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking alphasynuclein. J Neurosci 22: 8797–8807.

    CAS  PubMed  Google Scholar 

  • Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, Heaton RK, Group HNRC (2004). Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection. J Clin Exp Neuropsychol 26: 307–319.

    Article  PubMed  Google Scholar 

  • Daily A, Nath A, Hersh LB (2006). Tat peptides inhibit neprilysin. J NeuroVirol 12: 153–160.

    Article  CAS  PubMed  Google Scholar 

  • Everall IP, Heaton RK, Marcotte TD, Ellis RJ, McCutchan JA, Atkinson JH, Grant I, Mallory M, Masliah E (1999). Cortical synaptic density is reduced in mild to moderate human immunodeficiency virus neurocognitive disorder. HNRC Group. HIV Neurobehavioral Research Center. Brain Pathol 9: 209–217.

    Article  CAS  PubMed  Google Scholar 

  • Gai WP, Yuan HX, Li XQ, Power JT, Blumbergs PC, Jensen PH (2000). In situ and in vitro study of colocalization and segregation of alpha-synuclein, ubiquitin, and lipids in Lewy bodies. Exp Neurol 166: 324–333.

    Article  CAS  PubMed  Google Scholar 

  • Green DA, Masliah E, Vinters HV, Beizai P, Moore DJ, Achim CL (2005). Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. AIDS 19: 407–411.

    Article  CAS  PubMed  Google Scholar 

  • Hashimoto M, Hsu LJ, Xia Y, Takeda A, Sisk A, Sundsmo M, Masliah E (1999). Oxidative stress induces amyloidlike aggregate formation of NACP/alpha-synuclein in vitro. Neuroreport 10: 717–721.

    Article  CAS  PubMed  Google Scholar 

  • Liao YF, Wang BJ, Cheng HT, Kuo LH, Wolfe MS (2004). Tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma stimulate gamma-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway. J Biol Chem 279: 49523–49532.

    Article  CAS  PubMed  Google Scholar 

  • Mankowski JL, Queen SE, Tarwater PM, Fox KJ, Perry VH (2002). Accumulation of beta-amyloid precursor protein in axons correlates with CNS expression of SIV gp41. J Neuropathol Exp Neurol 61: 85–90.

    CAS  PubMed  Google Scholar 

  • Masliah E, DeTeresa RM, Mallory ME, Hansen LA (2000). Changes in pathological findings at autopsy in AIDS cases for the last 15 years. AIDS 14: 69–74.

    Article  CAS  PubMed  Google Scholar 

  • Masliah E, Heaton RK, Marcotte TD, Ellis RJ, Wiley CA, Mallory M, Achim CL, McCutchan JA, Nelson JA, Atkinson JH, Grant I (1997a). Dendritic injury is a pathological substrate for Human Immunodeficiency Virus-related cognitive disorders. Ann Neurol 42: 963–972.

    Article  CAS  PubMed  Google Scholar 

  • Masliah E, Westland CE, Rockenstein EM, Abraham CR, Mallory M, Veinberg I, Sheldon E, Mucke L (1997b). Amyloid precursor proteins protect neurons of transgenic mice against acute and chronic excitotoxic injuries in vivo. Neuroscience 78: 135–146.

    Article  CAS  PubMed  Google Scholar 

  • Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, d’Arminio Monforte A, Yust I, Bruun JN, Phillips AN, Lundgren JD (1998). Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 352: 1725–1730.

    Article  CAS  PubMed  Google Scholar 

  • Moore DJ, Masliah E, Rippeth JD, Gonzalez R, Carey CL, Cherner M, Ellis RJ, Achim CL, Marcotte TD, Heaton RK, Grant I, Group HNRC (2006). Cortical and subcortical neurodegeneration is associated with HIV neurocognitive impairment. AIDS 20: 879–887.

    Article  PubMed  Google Scholar 

  • Morgello S, Gelman BB, Kozlowski PB, Vinters HV, Masliah E, Cornford M, Cavert W, Marra C, Grant I, Singer EJ (2001). The National NeuroAIDS Tissue Consortium: a new paradigm in brain banking with an emphasis on infectious disease. Neuropathol Appl Neurobiol 27: 326–335.

    Article  CAS  PubMed  Google Scholar 

  • Murphy DD, Rueter SM, Trojanowski JQ, Lee VM (2000). Synucleins are developmentally expressed, and alphasynuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20: 3214–3220.

    CAS  PubMed  Google Scholar 

  • Piccinini M, Rinaudo MT, Anselmino A, Buccinna B, Ramondetti C, Dematteis A, Ricotti E, Palmisano L, Mostert M, Tovo PA (2005). The HIV protease inhibitors nelfinavir and saquinavir, but not a variety of HIV reverse transcriptase inhibitors, adversely affect human proteasome function. Antivir Ther 10: 215–223.

    CAS  PubMed  Google Scholar 

  • Ramage SN, Anthony IC, Carnie FW, Busuttil A, Robertson R, Bell JE (2005). Hyperphosphorylated tau and amyloid precursor protein deposition is increased in the brains of young drug abusers. Neuropathol Appl Neurobiol 31: 439–448.

    Article  CAS  PubMed  Google Scholar 

  • Reger M, Welsh R, Razani J, Martin DJ, Boone KB (2002). A meta-analysis of the neuropsychological sequelae of HIV infection. J Int Neuropsychol Soc. 8: 410–424.

    Article  PubMed  Google Scholar 

  • Rempel HC, Pulliam L (2005). HIV-1 Tat inhibits neprilysin and elevates amyloid beta. AIDS 19: 127–135.

    Article  CAS  PubMed  Google Scholar 

  • Snyder H, Mensah K, Theisler C, Lee J, Matouschek A, Wolozin B (2003). Aggregated and monomeric alphasynuclein bind to the S6′ proteasomal protein and inhibit proteasomal function. J Biol Chem 278: 11753–11759.

    Article  CAS  PubMed  Google Scholar 

  • Souza JM, Giasson BI, Chen Q, Lee VM, Ischiropoulos H (2000). Dityrosine cross-linking promotes formation of stable alpha-synuclein polymers. Implication of nitrative and oxidative stress in the pathogenesis of neurodegenerative synucleinopathies. J Biol Chem 275: 18344–18349.

    Article  CAS  PubMed  Google Scholar 

  • Spillantini MG, Crowther RA, Jakes R, Hasegawa M, Goedert M (1998). alpha-Synuclein in filamentous inclusions of Lewy bodies from Parkinson’s disease and dementia with lewy bodies. Proc Natl Acad Sci U S A 95: 6469–6473.

    Article  CAS  PubMed  Google Scholar 

  • Spillantini MG, Schmidt ML, Lee VM, Trojanowski JQ, Jakes R, Goedert M (1997). Alpha-synuclein in Lewy bodies. Nature 388: 839–840.

    Article  CAS  PubMed  Google Scholar 

  • Tsuboi Y, Ahlskog JE, Apaydin H, Parisi JE, Dickson DW (2001). Lewy bodies are not increased in progressive supranuclear palsy compared with normal controls. Neurology 57: 1675–1678.

    CAS  PubMed  Google Scholar 

  • Woods SP, Rippeth JD, Frol AB, Levy JK, Ryan E, Soukup VM, Hinkin CH, Lazzaretto D, Cherner M, Marcotte TD, Gelman BB, Morgello S, Singer EJ, Grant I, Heaton RK (2004). Interrater reliability of clinical ratings and neurocognitive diagnoses in HIV. J Clin Exp Neuropsychol 26: 759–778.

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Division of Neuropathology, David Geffen School of Medicine, Ronald Reagan UCLA Medical Center, Los Angeles, California, USA

    Negar Khanlou

  2. Department of Psychiatry, University of California, San Diego, California, USA

    David J. Moore, Gursharan Chana, Mariana Cherner, Sharron Dawes, Igor Grant & Ian P. Everall

  3. Department of Neuroscience, University of California, San Diego, California, USA

    Eliezer Masliah

  4. Department of Pathology, University of California, San Diego, California, USA

    Eliezer Masliah

  5. Department of HIV Neurobehavioral Research Center (HNRC), University of California, San Diego, California, USA

    Deborah Lazzaretto

Authors
  1. Negar Khanlou
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  2. David J. Moore
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  3. Gursharan Chana
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  4. Mariana Cherner
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  5. Deborah Lazzaretto
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  6. Sharron Dawes
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  7. Igor Grant
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  8. Eliezer Masliah
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  9. Ian P. Everall
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the HNRC Group

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Correspondence to Ian P. Everall.

Additional information

Drs. N. Khanlou and D. J. Moore are serving as joint first authors.

This work was supported by NIMH Center grant MH62512 and the California NeuroAIDS Tissue Network (CNTN) grants R24 MH59745 and U01 MH083506.

The HIV Neurobehavioral Research Center (HNRC) is supported by Center award MH 62512 from NIMH. The San Diego HIV Neurobehavioral Research Center (HNRC) group is affiliated with the University of California, San Diego, the Naval Hospital, San Diego, and the Veterans Affairs San Diego Healthcare System, and includes Director: Igor Grant, MD; Co-Directors: J. Hampton Atkinson, MD, Ronald J. Ellis, MD, PhD, and J. Allen McCutchan, MD; Center Manager: Thomas D. Marcotte, PhD; Heather Bentley, CCRA; Melanie Sherman; Naval Hospital San Diego: Braden R. Hale, MD, MPH (P.I.); Neuromedical Component: Ronald J. Ellis, MD, PhD (P.I.), J. Allen McCutchan, MD, Scott Letendre, MD, Edmund Capparelli, PharmD, Rachel Schrier, PhD; Jennifer Marquie-Beck; Terry Alexander, RN; Janis Durelle; Neurobehavioral Component: Robert K. Heaton, PhD (P.I.), Mariana Cherner, PhD, Steven Paul Woods, PsyD, David J. Moore, PhD; Matthew Dawson; Neuroimaging Component: Terry Jernigan, PhD (P.I.), Christine Fennema-Notestine, PhD, Sarah L. Archibald, MA, John Hesselink, MD, Jacopo Annese, PhD, Michael J. Taylor, PhD, Brian Schweinsburg, PhD; Neurobiology Component: Eliezer Masliah, MD (P.I.), Ian Everall, FRCPsych, FRCPath, PhD, Cristian Achim, MD, PhD; Neurovirology Component: Douglas Richman, MD, (P.I.), David M. Smith, MD; International Component: J. Allen McCutchan, MD (P.I.); Developmental Component: Ian Everall, FRCPsych., FRCPath., PhD (P.I.), Stuart Lipton, MD, PhD; Clinical Trials Component: J. Allen McCutchan, MD, J. Hampton Atkinson, MD, Ronald J. Ellis, MD, PhD, Scott Letendre, MD; Participant Accrual and Retention Unit: J. Hampton Atkinson, MD (P.I.), Rodney von Jaeger, MPH; Data Management Unit: Anthony C. Gamst, PhD (P.I.), Clint Cushman (Data Systems Manager), Daniel R. Masys, MD (Senior Consultant); Statistics Unit: Ian Abramson, PhD (P.I.), Florin Vaida, PhD, Christopher Ake, PhD.

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Khanlou, N., Moore, D.J., Chana, G. et al. Increased frequency of α-synuclein in the substantia nigra in human immunodeficiency virus infection. Journal of NeuroVirology 15, 131–138 (2009). https://doi.org/10.1080/13550280802578075

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  • DOI: https://doi.org/10.1080/13550280802578075

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