老年载脂蛋白 E- PON1 缺陷小鼠的阿尔茨海默病标志物。

Alzheimer's Disease Markers in Aged ApoE-PON1 Deficient Mice.

机构信息

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Orlando, FL, USA.

出版信息

J Alzheimers Dis. 2019;67(4):1353-1365. doi: 10.3233/JAD-180883.

DOI:10.3233/JAD-180883

PMID:30714958

Abstract

BACKGROUND

Alzheimer's disease (AD) is a neurodegenerative disorder associated with aging. Cardiovascular risk factors like hypertension and atherosclerosis increase the risk for AD. Polymorphic alleles of apolipoprotein E (ApoE) are one of the main genetic determinants of AD.

OBJECTIVE

Mice, double-knockout (DKO) for ApoE (major cholesterol carrier in brain) and PON1 (paroxonase1, reduces oxidative stress), showed severe age-dependent atherosclerosis of the arteries carrying blood to the brain even on normal diet. This prompted us to investigate the possibility of an AD pathology resulting from the deficiency of ApoE and the induction of oxidative stress.

METHODS

Atherosclerotic lesions were quantified by ImageJ. The brain hippocampus of young and old ApoE-PON1 DKO mice and control mice were harvested. RT-PCR analysis was performed for mRNA levels of AD specific markers. Blood levels of S100 calcium-binding protein B (S100B) protein were measured by ELISA. H&E as well as immunostaining was performed to detect amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs) in brain tissues. Evans blue dye was used to evaluate the vascular permeability and blood-brain barrier (BBB) dysfunction.

RESULTS

Results showed that the older DKO mice had severe carotid atherosclerosis, increased mRNA levels of AD markers in brain tissue, and elevated levels of serum S100B protein. Immunological staining confirmed the characteristics of AD. Ex-vivo imaging showed higher levels of Evans blue dye in the ApoE-PON1 DKO mice brain tissues, pointing toward impaired vasculature.

CONCLUSION

Aged ApoE-PON1 DKO mice displaying AD specific markers along with Aβ plaques, NFTs, and disrupted BBB suggests the animals are suffering from AD.

摘要

背景

阿尔茨海默病（AD）是一种与衰老相关的神经退行性疾病。高血压和动脉粥样硬化等心血管危险因素会增加 AD 的风险。载脂蛋白 E（apoE）的多态等位基因是 AD 的主要遗传决定因素之一。

目的

apoE（大脑中主要的胆固醇载体）和 PON1（对氧磷酶 1，降低氧化应激）双重敲除（DKO）的小鼠即使在正常饮食下，也会出现严重的与年龄相关的向大脑供血的动脉粥样硬化。这促使我们研究 apoE 缺乏和氧化应激诱导是否会导致 AD 病理。

方法

通过 ImageJ 定量分析动脉粥样硬化病变。采集年轻和年老 apoE-PON1 DKO 小鼠和对照小鼠的大脑海马体。通过 RT-PCR 分析 AD 特异性标志物的 mRNA 水平。通过 ELISA 测量 S100 钙结合蛋白 B（S100B）蛋白的血清水平。进行 H&E 染色和免疫染色以检测脑组织中的淀粉样-β（Aβ）斑块和神经原纤维缠结（NFTs）。使用 Evans 蓝染料评估血管通透性和血脑屏障（BBB）功能障碍。