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.
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 C57B6/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.
Aliev
Gjumrakch
G
Microscopy Research Center, Department of Anatomy, Case Western Reserve University and University Hospitals of Cleveland, 2085 Adelbert Road, Cleveland, OH 44106, USA. gxa15@po.cwru.edu
Seyidova
Dilara
D
Neal
Maxwell L
ML
Shi
Jiong
J
Lamb
Bruce T
BT
Siedlak
Sandra L
SL
Vinters
Harry V
HV
Head
Elizabeth
E
Perry
George
G
Lamanna
Joseph C
JC
Friedland
Robert P
RP
Cotman
Carl W
CW
D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001161:Arteriosclerosis / Q000473:pathology*; D001483:Base Sequence; D002561:Cerebrovascular Disorders / Q000473:pathology*; D015342:DNA Probes; D004272:DNA, Mitochondrial / Q000235:genetics*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008833:Microcirculation / Q000473:pathology*; D023421:Models, Animal; D018384:Oxidative Stress; D017384:Sequence Deletion
D016564:Amyloid beta-Protein Precursor; D015342:DNA Probes; D004272:DNA, Mitochondrial