载脂蛋白 A-I 基因敲除可减少阿尔茨海默病 Tg2576 小鼠模型的实质和血管β-淀粉样蛋白病理。

Knockout of apolipoprotein A-I decreases parenchymal and vascular β-amyloid pathology in the Tg2576 mouse model of Alzheimer's disease.

机构信息

School of Life, Health and Chemical Sciences, STEM Faculty, The Open University, Milton Keynes, UK.

Clinical and Experimental Sciences, Faculty of Medicine, University of Southampton, Southampton, UK.

出版信息

Neuropathol Appl Neurobiol. 2019 Dec;45(7):698-714. doi: 10.1111/nan.12556. Epub 2019 May 14.

DOI:10.1111/nan.12556

PMID:31002190

Abstract

AIMS

Apolipoprotein A-I (apoA-I), the principal apolipoprotein associated with high-density lipoproteins in the periphery, is also found at high concentrations in the cerebrospinal fluid. Previous studies have reported either no impact or vascular-specific effects of apoA-I knockout (KO) on β-amyloid (Aβ) pathology. However, the putative mechanism(s) by which apoA-I may influence Aβ deposition is unknown.

METHODS

We evaluated the effect of apoA-I deletion on Aβ pathology, Aβ production and clearance from the brain in the Tg2576 mouse model of Alzheimer's disease (AD).

RESULTS

Contrary to previous reports, deletion of the APOA1 gene significantly reduced concentrations of insoluble Aβ40 and Aβ42 and reduced plaque load in both the parenchyma and blood vessels of apoA-I KO × Tg2576 mice compared to Tg2576 animals. This was not due to decreased Aβ production or alterations in Aβ species. Levels of soluble clusterin/apoJ were significantly higher in neurons of apoA-I KO mice compared to both wildtype (WT) and apoA-I KO × Tg2576 mice. In addition, clearance of Aβ along intramural periarterial drainage pathways was significantly higher in apoA-I KO mice compared to WT animals.

CONCLUSION

These data suggest that deletion of apoA-I is associated with increased clearance of Aβ and reduced parenchymal and vascular Aβ pathology in the Tg2576 model. These results suggest that peripheral dyslipidaemia can modulate the expression of apolipoproteins in the brain and may influence Aβ clearance and aggregation in AD.

摘要

目的

载脂蛋白 A-I（apoA-I）是外周高密度脂蛋白中主要的载脂蛋白，也在脑脊液中高浓度存在。先前的研究报告称 apoA-I 敲除（KO）对β-淀粉样蛋白（Aβ）病理没有影响或具有血管特异性影响。然而，apoA-I 影响 Aβ 沉积的潜在机制尚不清楚。

方法

我们评估了 apoA-I 缺失对阿尔茨海默病（AD）Tg2576 小鼠模型中 Aβ 病理学、Aβ 产生和大脑清除的影响。

结果

与先前的报告相反，apoA1 基因缺失显著降低了不溶性 Aβ40 和 Aβ42 的浓度，并降低了 apoA-I KO×Tg2576 小鼠实质和血管中的斑块负荷，与 Tg2576 动物相比。这不是由于 Aβ 产生减少或 Aβ 种类改变引起的。apoA-I KO 小鼠神经元中的可溶性载脂蛋白 J/簇蛋白水平明显高于野生型（WT）和 apoA-I KO×Tg2576 小鼠。此外，apoA-I KO 小鼠沿壁内动脉周围排水途径的 Aβ 清除率明显高于 WT 动物。