Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: reversal with beclin-1 gene transfer.
Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: reversal with beclin-1 gene transfer.
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DOI：
10.1007/s13365-012-0145-7
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发表时间：
2013-02
影响因子：
3.2
通讯作者：
Masliah, Eliezer
中科院分区：
文献类型：
--
作者：
Fields, Jerel;Dumaop, Wilmar;Rockenstein, Edward;Mante, Michael;Spencer, Brian;Grant, Igor;Ellis, Ron;Letendre, Scott;Patrick, Christina;Adame, Anthony;Masliah, Eliezer
年龄（>50岁）的人类免疫缺陷病毒（HIV）患者是美国HIV感染人群中增长最快的部分，并且尽管有抗逆转录病毒疗法，在这一群体中，HIV相关神经认知障碍（HAND）的患病率仍有所增加或保持不变。自噬是一种针对聚集蛋白和老化细胞器的细胞内清除途径；自噬失调与帕金森病、阿尔茨海默病和HAND的发病机制有关。在此，我们假设自噬失调可能导致HIV感染者中与衰老相关的神经病理学变化。为了探究这种可能性，我们检测了一组特征明确的<50岁（年轻）和>50岁（老年）的HIV阳性以及HIV脑炎（HIVE）患者的尸检大脑样本中的自噬标记物水平。详细的临床和神经病理学数据显示，年轻和老年HIVE患者都有更高的病毒载量、增加的神经炎症以及升高的神经退行性变；然而，老年HIVE患者的尸检大脑组织显示出最严重的神经退行性病理改变。有趣的是，年轻的HIVE患者表现出beclin - 1、组织蛋白酶D和轻链（LC）3的增加，但与年龄匹配的HIV阳性供体相比，这些自噬标记物在老年HIVE病例中减少。在老年gp120转基因（tg）小鼠中观察到了类似的自噬标记物变化；老年gp120 tg小鼠中beclin - 1和LC3减少，而mTor水平升高。慢病毒介导的beclin - 1基因转移（已知可激活自噬途径）增加了老年gp120 tg小鼠中beclin - 1、LC3和微管相关蛋白2的表达，同时降低了胶质纤维酸性蛋白和Iba1的表达。这些数据表明年轻和老年HIVE患者自噬途径存在差异改变，并且自噬的重新激活可能改善这些患者的神经退行性表型。
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.
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影响因子：
6.7
作者：
Grégoire IP;Richetta C;Meyniel-Schicklin L;Borel S;Pradezynski F;Diaz O;Deloire A;Azocar O;Baguet J;Le Breton M;Mangeot PE;Navratil V;Joubert PE;Flacher M;Vidalain PO;André P;Lotteau V;Biard-Piechaczyk M;Rabourdin-Combe C;Faure M
通讯作者：
Faure M
影响因子：
3.2
作者：
Heaton, Robert K.;Franklin, Donald R.;Ellis, Ronald J.;McCutchan, J. Allen;Letendre, Scott L.;LeBlanc, Shannon;Corkran, Stephanie H.;Duarte, Nichole A.;Clifford, David B.;Woods, Steven P.;Collier, Ann C.;Marra, Christina M.;Morgello, Susan;Mindt, Monica Rivera;Taylor, Michael J.;Marcotte, Thomas D.;Atkinson, J. Hampton;Wolfson, Tanya;Gelman, Benjamin B.;McArthur, Justin C.;Simpson, David M.;Abramson, Ian;Gamst, Anthony;Fennema-Notestine, Christine;Jernigan, Terry L.;Wong, Joseph;Grant, Igor
通讯作者：
Grant, Igor
影响因子：
3.7
作者：
Crews L;Spencer B;Desplats P;Patrick C;Paulino A;Rockenstein E;Hansen L;Adame A;Galasko D;Masliah E
通讯作者：
Masliah E
影响因子：
2.8
作者：
Erlandson, Kristine M.;Allshouse, Amanda A.;Campbell, Thomas B.
通讯作者：
Campbell, Thomas B.
影响因子：
1.5
作者：
Haas, DW;Clough, LA;Larder, B
通讯作者：
Larder, B