Document Detail


Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: reversal with beclin-1 gene transfer.
MedLine Citation:
PMID:  23341224     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Aged (>50 years old) human immunodeficiency virus (HIV) patients are the fastest-growing segment of the HIV-infected population in the USA and despite antiretroviral therapy, HIV-associated neurocognitive disorder (HAND) prevalence has increased or remained the same among this group. Autophagy is an intracellular clearance pathway for aggregated proteins and aged organelles; dysregulation of autophagy is implicated in the pathogenesis of Parkinson's disease, Alzheimer's disease, and HAND. Here, we hypothesized that dysregulated autophagy may contribute to aging-related neuropathology in HIV-infected individuals. To explore this possibility, we surveyed autophagy marker levels in postmortem brain samples from a cohort of well-characterized <50 years old (young) and >50 years old (aged) HIV+ and HIV encephalitis (HIVE) patients. Detailed clinical and neuropathological data showed the young and aged HIVE patients had higher viral load, increased neuroinflammation and elevated neurodegeneration; however, aged HIVE postmortem brain tissues showed the most severe neurodegenerative pathology. Interestingly, young HIVE patients displayed an increase in beclin-1, cathepsin-D and light chain (LC)3, but these autophagy markers were reduced in aged HIVE cases compared to age-matched HIV+ donors. Similar alterations in autophagy markers were observed in aged gp120 transgenic (tg) mice; beclin-1 and LC3 were decreased in aged gp120 tg mice while mTor levels were increased. Lentivirus-mediated beclin-1 gene transfer, that is known to activate autophagy pathways, increased beclin-1, LC3, and microtubule-associated protein 2 expression while reducing glial fibrillary acidic protein and Iba1 expression in aged gp120 tg mice. These data indicate differential alterations in the autophagy pathway in young versus aged HIVE patients and that autophagy reactivation may ameliorate the neurodegenerative phenotype in these patients.
Authors:
Jerel Fields; Wilmar Dumaop; Edward Rockenstein; Michael Mante; Brian Spencer; Igor Grant; Ron Ellis; Scott Letendre; Christina Patrick; Anthony Adame; Eliezer Masliah
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-24
Journal Detail:
Title:  Journal of neurovirology     Volume:  19     ISSN:  1538-2443     ISO Abbreviation:  J. Neurovirol.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-08     Completed Date:  2013-08-09     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  9508123     Medline TA:  J Neurovirol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  89-101     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
AIDS Dementia Complex / genetics,  metabolism*,  pathology
Adult
Age Factors
Animals
Apoptosis Regulatory Proteins / analysis,  biosynthesis*
Autophagy / physiology*
Blotting, Western
Female
Gene Transfer Techniques
Genetic Therapy / methods*
HIV Envelope Protein gp120
Humans
Immunohistochemistry
Male
Membrane Proteins / analysis,  biosynthesis*
Mice
Mice, Transgenic
Microscopy, Confocal
Middle Aged
Grant Support
ID/Acronym/Agency:
AG043384/AG/NIA NIH HHS; MH062962/MH/NIMH NIH HHS; MH5974/MH/NIMH NIH HHS; MH83506/MH/NIMH NIH HHS; P01 AG031097/AG/NIA NIH HHS; P30 MH062512/MH/NIMH NIH HHS; P30 NS076411/NS/NINDS NIH HHS; P50 MH045294/MH/NIMH NIH HHS; R01 AG043384/AG/NIA NIH HHS; R01 MH062962/MH/NIMH NIH HHS; U01 MH083506/MH/NIMH NIH HHS; U24 MH100928/MH/NIMH NIH HHS
Chemical
Reg. No./Substance:
0/Apoptosis Regulatory Proteins; 0/BECN1 protein, human; 0/Becn1 protein, mouse; 0/HIV Envelope Protein gp120; 0/Membrane Proteins
Comments/Corrections

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