衰老和脑游离胆固醇浓度对豚鼠淀粉样β肽积累的影响

IF 1.7 4区 医学 Q3 PHARMACOLOGY & PHARMACY
K. Sandy Pang, H. Benson Peng, Betty P. Li, Binyu Wen, Keumhan Noh, Runyu Xia, Anja Toscan, Sylvia Serson, Paul E. Fraser, Rommel G. Tirona, Inès A. M. de Lannoy
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引用次数: 0

摘要

阿尔茨海默病是一种复杂的多因素神经退行性疾病,年龄是其主要风险因素。哈特利豚鼠(GP)的淀粉样-β(Aβ40和Aβ42)肽、Mdr1和APP(淀粉样前体蛋白)的序列与人类高度同源,脂质处理与人类相似。P-gp(Abcb1)和Cyp46a1(24(S)-羟化酶)分别负责Aβ40和Aβ42的外流和胆固醇代谢,它们的蛋白表达水平随着年龄的增长而下降,而Lrp1(低密度脂蛋白受体相关蛋白1)的蛋白表达水平则随着年龄的增长而下降、而 Lrp1(低密度脂蛋白受体相关蛋白 1)、Rage(高级糖化终产物受体)和 Abca1(ATP 结合盒 A 亚家族成员 1)的胆固醇流出量则在所研究的年龄段中保持不变。脑 Aβ 肽浓度和 Abca1 蛋白表达水平与游离胆固醇呈强烈的负相关。然而,Aβ肽浓度与Cyp46a1的相关性并不显著,24(S)-羟基胆固醇代谢物的浓度从20周大的豚鼠到40周大的豚鼠呈下降趋势。综合数据表明,游离胆固醇对脑 Aβ 的积累有一定作用。P-gp 和 Lrp1 蛋白水平的下降会进一步加剧 Aβ 肽在豚鼠大脑中的积累。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs

Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs

Aging and brain free cholesterol concentration on amyloid-β peptide accumulation in guinea pigs

Alzheimer’s disease is a complex multifactorial neurodegenerative disorder wherein age is a major risk factor. The appropriateness of the Hartley guinea pig (GP), which displays high sequence homologies of its amyloid-β (Aβ40 and Aβ42) peptides, Mdr1 and APP (amyloid precursor protein) and similarity in lipid handling to humans, was appraised among 9–40 weeks old guinea pigs. Protein expression levels of P-gp (Abcb1) and Cyp46a1 (24(S)-hydroxylase) for Aβ40, and Aβ42 efflux and cholesterol metabolism, respectively, were decreased with age, whereas those for Lrp1 (low-density lipoprotein receptor related protein 1), Rage (receptor for advanced glycation endproducts) for Aβ efflux and influx, respectively, and Abca1 (the ATP binding cassette subfamily A member 1) for cholesterol efflux, were unchanged among the ages examined. There was a strong, negative correlation of the brain Aβ peptide concentrations and Abca1 protein expression levels with free cholesterol. The correlation of Aβ peptide concentrations with Cyp46a1 was, however, not significant, and concentrations of the 24(S)-hydroxycholesterol metabolite revealed a decreasing trend from 20 weeks old toward 40 weeks old guinea pigs. The composite data suggest a role for free cholesterol on brain Aβ accumulation. The decreases in P-gp and Lrp1 protein levels should further exacerbate the accumulation of Aβ peptides in guinea pig brain.

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来源期刊
CiteScore
3.60
自引率
0.00%
发文量
35
审稿时长
6-12 weeks
期刊介绍: Biopharmaceutics & Drug Dispositionpublishes original review articles, short communications, and reports in biopharmaceutics, drug disposition, pharmacokinetics and pharmacodynamics, especially those that have a direct relation to the drug discovery/development and the therapeutic use of drugs. These includes: - animal and human pharmacological studies that focus on therapeutic response. pharmacodynamics, and toxicity related to plasma and tissue concentrations of drugs and their metabolites, - in vitro and in vivo drug absorption, distribution, metabolism, transport, and excretion studies that facilitate investigations related to the use of drugs in man - studies on membrane transport and enzymes, including their regulation and the impact of pharmacogenomics on drug absorption and disposition, - simulation and modeling in drug discovery and development - theoretical treatises - includes themed issues and reviews and exclude manuscripts on - bioavailability studies reporting only on simple PK parameters such as Cmax, tmax and t1/2 without mechanistic interpretation - analytical methods
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