Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels as a central target for the development of human AD and AD-Like pathology in aged transgenic mice

被引:70
作者
Aliev, G
Seyidova, D
Neal, ML
Shi, J
Lamb, BT
Siedlak, SL
Vinters, HV
Head, E
Perry, G
Lamanna, JC
Friedland, RP
Cotman, CW
机构
[1] Case Western Reserve Univ, Inst Pathol, Microscopy Res Ctr, Cleveland, OH 44106 USA
[2] Case Western Reserve Univ, Dept Anat, Cleveland, OH 44106 USA
[3] Case Western Reserve Univ, Dept Pathol, Cleveland, OH 44106 USA
[4] Case Western Reserve Univ, Dept Neurol, Cleveland, OH 44106 USA
[5] Case Western Reserve Univ, Dept Genet, Cleveland, OH 44106 USA
[6] Univ Hosp Cleveland, Cleveland, OH 44106 USA
[7] Univ Calif Los Angeles, Los Angeles, CA USA
[8] Univ Calif Irvine, Irvine, CA USA
来源
ALZHEIMER'S DISEASE: VASCULAR ETIOLOGY AND PATHOLOGY | 2002年 / 977卷
关键词
Alzheimer's disease; vascular factors; free radicals; metabolism; mitochondria; neurodegeneration; oxidative stress;
D O I
10.1111/j.1749-6632.2002.tb04798.x
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
We have studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD brain biopsy, human short postmortem brain tissues, and yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (AbetaPP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5 kb deleted, and mouse mtDNA was performed, along with immunocytochemistry using antibodies against amyloid precursor protein (APP), 8-hydroxy-2'-guanosine (8-OHG), and cytochrome c oxidase,(COX). There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC, and C57B6/SJL Tg (+) mice compared to age-matched controls. In addition, vessels with more severe lesions showed immunopositive staining for APP and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells (EC). Significantly more mitochondrial abnormalities were seen in human AD, YAC, and C57B6/SJL Tg (+) mouse microvessels where lesions occurred. In situ hybridization using wild and chimera (5 kb) mtDNA probes revealed positive signals in damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels close to regions' of large amyloid deposition. These features were absent in undamaged regions of human AD tissues, YAC and C57136/SJL Tg (+) mouse tissues, and in age-matched control subjects. In addition, vessels with atherosclerotic lesions revealed endothelium and perivascular cells possessing clusters of wild and deleted mtDNA positive probes. These mtDNA deletions were accompanied by increased amounts of immunoreactive APP, 8-OHG, and COX in the same cellular compartment. Our observations demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress-induced damage.
引用
收藏
页码:45 / 64
页数:20
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