CCR5 antagonist reduces HIV-induced amyloidogenesis, tau pathology, neurodegeneration, and blood-brain barrier alterations in HIV-infected hu-PBL-NSG mice.
CCR5 antagonist reduces HIV-induced amyloidogenesis, tau pathology, neurodegeneration, and blood-brain barrier alterations in HIV-infected hu-PBL-NSG mice.
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CCR5拮抗剂减少了HIV感染的HU-PBL-NSG小鼠中HIV诱导的淀粉样生成，TAU病理学，神经变性和血脑屏障的改变。
DOI：
10.1186/s13024-021-00500-0
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发表时间：
2021-11-22
影响因子：
15.1
通讯作者：
Kanmogne GD
中科院分区：
文献类型：
--
作者：
Bhargavan B;Woollard SM;McMillan JE;Kanmogne GD
神经认知障碍存在于50%的HIV感染个体中，并且通常与阿尔茨海默病（AD）样脑病理学相关，包括淀粉样蛋白-β（A β）增加和Tau过度磷酸化。在此，我们的目的是确定HIV-1感染是否会导致HIV/AIDS人源化小鼠模型中的AD样病理，以及CCR5拮抗剂马拉韦罗是否会改变HIV诱导的病理。移植人血白细胞的NOD/scid-IL-2R γ cnull小鼠感染HIV-1，不给药或接受马拉韦罗（120 mg/kg，每日两次）给药。每周通过流式细胞术定量动物血液中的人细胞。在感染后第3周处死动物;使用p24抗原ELISA、RNAscope和qPCR定量血液和组织病毒载量。人（HLA-DR+）细胞、A β-42、磷酸化Tau、神经元标记物（MAP 2、NeuN、神经丝-L）、γ-分泌酶激活蛋白（GSAP）和血脑屏障（BBB）紧密连接（TJ）通过免疫组织化学、免疫荧光、免疫印迹和qPCR定量脑组织中的蛋白表达和转录。ELISA法测定血浆A β-42、A β-42细胞摄取、释放和跨内皮转运。HIV-1显著降低人（h）CD4 + T细胞和hCD4/hCD8比率;降低BBB TJ蛋白claudin-5、ZO-1、ZO-2的表达;并增加脑组织中的HLA-DR+细胞。值得注意的是，HIV感染的动物显示血浆和脑A β-42和磷酸化Tau（苏氨酸181、苏氨酸231、丝氨酸396、丝氨酸199）增加，这与GSAP（一种催化A β形成的酶）的转录上调以及MAP 2、NeuN和neuroadherent-L的丢失有关。马拉韦罗治疗显著降低血液和脑病毒载量，防止HIV诱导的神经元标志物和TJ蛋白丢失;减少脑组织中HLA-DR+细胞浸润，显著降低HIV诱导的A β-42、GSAP和磷酸化Tau增加。马拉韦罗还可减少人巨噬细胞中的A β滞留并增加A β释放;降低人脑内皮细胞中晚期糖基化终末产物（AGEs）的受体并增加低密度脂蛋白受体相关蛋白-1（LRP 1）的表达。Maraviroc可诱导A β跨内皮转运，LRP 1拮抗剂可阻断该转运，但β受体拮抗剂不能阻断该转运。Maraviroc显著减少HIV诱导的淀粉样蛋白生成、GSAP、磷酸化Tau、神经变性、BBB改变和白细胞浸润至CNS。马拉韦罗通过LRP 1途径增加细胞A β流出和跨内皮A β转运。因此，治疗靶向CCR5可以减少病毒血症，保护BBB和神经元，增加脑A β流出，并减少AD样神经病变。在线版本包含补充材料，可通过10.1186/s13024 - 021 - 00500 - 0获得。
Neurocognitive impairment is present in 50% of HIV-infected individuals and is often associated with Alzheimer’s Disease (AD)-like brain pathologies, including increased amyloid-beta (Aβ) and Tau hyperphosphorylation. Here, we aimed to determine whether HIV-1 infection causes AD-like pathologies in an HIV/AIDS humanized mouse model, and whether the CCR5 antagonist maraviroc alters HIV-induced pathologies. NOD/scid–IL-2Rγcnull mice engrafted with human blood leukocytes were infected with HIV-1, left untreated or treated with maraviroc (120 mg/kg twice/day). Human cells in animal’s blood were quantified weekly by flow cytometry. Animals were sacrificed at week-3 post-infection; blood and tissues viral loads were quantified using p24 antigen ELISA, RNAscope, and qPCR. Human (HLA-DR+) cells, Aβ-42, phospho-Tau, neuronal markers (MAP 2, NeuN, neurofilament-L), gamma-secretase activating protein (GSAP), and blood-brain barrier (BBB) tight junction (TJ) proteins expression and transcription were quantified in brain tissues by immunohistochemistry, immunofluorescence, immunoblotting, and qPCR. Plasma Aβ-42, Aβ-42 cellular uptake, release and transendothelial transport were quantified by ELISA. HIV-1 significantly decreased human (h)CD4+ T-cells and hCD4/hCD8 ratios; decreased the expression of BBB TJ proteins claudin-5, ZO-1, ZO-2; and increased HLA-DR+ cells in brain tissues. Significantly, HIV-infected animals showed increased plasma and brain Aβ-42 and phospho-Tau (threonine181, threonine231, serine396, serine199), associated with transcriptional upregulation of GSAP, an enzyme that catalyzes Aβ formation, and loss of MAP 2, NeuN, and neurofilament-L. Maraviroc treatment significantly reduced blood and brain viral loads, prevented HIV-induced loss of neuronal markers and TJ proteins; decreased HLA-DR+ cells infiltration in brain tissues, significantly reduced HIV-induced increase in Aβ-42, GSAP, and phospho-Tau. Maraviroc also reduced Aβ retention and increased Aβ release in human macrophages; decreased the receptor for advanced glycation end products (RAGE) and increased low-density lipoprotein receptor–related protein-1 (LRP1) expression in human brain endothelial cells. Maraviroc induced Aβ transendothelial transport, which was blocked by LRP1 antagonist but not RAGE antagonist. Maraviroc significantly reduced HIV-induced amyloidogenesis, GSAP, phospho-Tau, neurodegeneration, BBB alterations, and leukocytes infiltration into the CNS. Maraviroc increased cellular Aβ efflux and transendothelial Aβ transport via LRP1 pathways. Thus, therapeutically targeting CCR5 could reduce viremia, preserve the BBB and neurons, increased brain Aβ efflux, and reduce AD-like neuropathologies. The online version contains supplementary material available at 10.1186/s13024-021-00500-0.
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影响因子：
3.2
作者：
Barber, T. J.;Imaz, A.;Gazzard, B.
通讯作者：
Gazzard, B.
DOI：
10.1177/1545109712462454
发表时间：
2013-01-01
影响因子：
--
作者：
Babiker, Zahir Osman Eltahir;Douthwaite, Sam Thomas;Wilkins, Edmund
通讯作者：
Wilkins, Edmund
DOI：
10.4049/jimmunol.1100211
发表时间：
2011-06-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Lan X;Xu J;Kiyota T;Peng H;Zheng JC;Ikezu T
通讯作者：
Ikezu T
影响因子：
11.2
作者：
Chu J;Wisniewski T;Praticò D
通讯作者：
Praticò D
影响因子：
4.8
作者：
Bhargavan B;Woollard SM;Kanmogne GD
通讯作者：
Kanmogne GD