β淀粉样蛋白间隙和p-Tau中CX3CR1和Fractalkine 趋化因子的影响累积在阿尔兹海默病啮齿动物模型中： Fractalkine是一个系统的AD生物标志物吗？

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.

Cite this article as:

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