摘要
小胶质细胞和星形胶质细胞因子是阿尔兹海默病(AD)的主要来源,δ趋化因子受体CX3CR1在小胶质细胞和神经元的配体中存在,Fractalkine有两个亚型:固定膜异构体和可溶性同种型。老年鼠脑细胞中降低的可溶性fractalkine水平可能是神经损失的结果。通过关联CX3CR1,可溶性的fractalkine维持小胶质细胞在一个合适的状态。CX3CR1基因在小鼠体内的消融过表达了人类淀粉样前体蛋白(APP / PS-1),从而增加了细胞因子的水平,增强了老鼠在病理学和恶化的行为表现。然而,CX3CR1缺陷导致了大脑内基因剂量依赖性Aβ间隙,并且诱发了小胶质细胞的活性,此外,CX3CR1缺陷可能通过3xTg模型内预防神经损失产生好的效果,实际上,通过诱导转基因AD模型中小胶质细胞选择性的protofibrillar淀粉样β蛋白吞噬作用,CX3CR1缺陷增加了小胶质细胞的phagocytosome活性。 此外,趋化因子膜异型在β-淀粉样蛋白清除和tau蛋白的沉积 中起着不同的作用,这种锚定膜FKN信号可能会增加淀粉样蛋白病变,可溶性Fractalkine水平可预防taupathies。然而,在人类的阿尔兹海默病中,唯一发表的研究报告显示在阿尔兹海默病认知障碍患者中有更高的系统Fractalkine水平。 在小鼠模型中,炎症激活的小胶质细胞加剧了tau的病理性。零趋化因子转基因小鼠的研究表明目标趋化因子膜异型APP/PS-1小鼠缺陷增强了神经元MAPT磷酸化,尽管他们减少了淀粉样蛋白的负担。可溶性Fractalkine的过表达与腺病毒载体降低了tau蛋白的病理变化,在taupathy的 Tg4510模型中,预防神经退行性疾病。 最后,带有Aβ (1-42)的动物被注射了慢病毒(皮质)或带有P301L突变的小鼠(额颞叶痴呆)
关键词: 阿尔茨海默病;β淀粉样蛋白;自噬;趋化因子;CX3CR1 / Fractalkine(CX3CL1);细胞因子;小胶质细胞;神经退行性疾病;神经炎症;神经保护;Tau。
Current Alzheimer Research
Title:Effects of CX3CR1 and Fractalkine Chemokines in Amyloid Beta Clearance and p-Tau Accumulation in Alzheimer,s Disease (AD) Rodent Models: Is Fractalkine a Systemic Biomarker for AD?
Volume: 13 Issue: 4
Author(s): Jose Joaquin Merino, Vilma Muneton-Gomez, Maria-Isabel Alvarez, Adolfo Toledano-Diaz
Affiliation:
关键词: 阿尔茨海默病;β淀粉样蛋白;自噬;趋化因子;CX3CR1 / Fractalkine(CX3CL1);细胞因子;小胶质细胞;神经退行性疾病;神经炎症;神经保护;Tau。
摘要: Microglia and astrocytes are the major source of cytokines in Alzheimer,s disease (AD). CX3CR1 is a delta chemokine receptor found in microglia and its neuronal ligand, Fractalkine, has two isoforms: an anchored-membrane isoform, and a soluble isoform. The reduced soluble fractalkine levels found in the brain (cortex/hippocampus) of aged rats, may be a consequence of neuronal loss. This soluble fractalkine maintains microglia in an appropiate state by interacting with CX3CR1. The ablation of the CX3CR1 gene in mice overexpressing human amyloid precursor protein (APP/PS-1) increased cytokine levels, enhanced Tau pathology and worsened behavioural performance in these mice. However, CX3CR1 deficiency resulted in a gene dose-dependent Aβ clearance in the brain, and induced microglial activation. In addition, CX3CR1 deficiency can have benefical effects by preventing neuronal loss in the 3xTg model. In fact, CX3CR1 deficiency increases microglial phagocytosome activity by inducing selective protofibrillar amyloid-beta phagocytosis in microglial cells in transgenic AD models.
On the other hand, the fractalkine membrane isoform plays a differential role in amyloid beta clearance and Tau deposition. This anchored membrane FKN signalling might increase amyloid pathology while soluble fractalkine levels could prevent taupathies. However, in human AD, the only published study has reported higher systemic fractalkine levels in AD patients with cognitive impairment.
In mouse models, inflammatory activation of microglia accelerates Tau pathology. Studies in transgenic mice with fractalkine null mice suggest that APP/PS-1 mice deficient for the anchored membrane-fractalkine isoform exhibited enhanced neuronal MAPT phosphorylation despite their reduced amyloid burden. The soluble fractalkine overexpression with adenoviral vectors reduced tau pathology and prevented neurodegeneration in a Tg4510 model of taupathy
Finally, animals with Aβ (1-42) infused by lentivirus (cortex) or mice with the P301L mutation (frontotemporal dementia) had caspase-3 activation (8-fold) and higher proinflammatory TNF alpha levels and p-Tau deposits at 4 weeks postinfusion.
Thus, the CX3CR1/Fractalkine axis regulates microglial activation, the clearance of amyloid plaque and plays a role in p-Tau intraneuronal accumulation in rodent models of AD.
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Jose Joaquin Merino, Vilma Muneton-Gomez, Maria-Isabel Alvarez, Adolfo Toledano-Diaz , Effects of CX3CR1 and Fractalkine Chemokines in Amyloid Beta Clearance and p-Tau Accumulation in Alzheimer,s Disease (AD) Rodent Models: Is Fractalkine a Systemic Biomarker for AD?, Current Alzheimer Research 2016; 13 (4) . https://dx.doi.org/10.2174/1567205013666151116125714
DOI https://dx.doi.org/10.2174/1567205013666151116125714 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
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