Address for correspondence: Gjumrakch Aliev, M.D., Ph.D., Microscopy Research Center, Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106. Voice: 216-368-6605; fax: 216-368-8649 or 216-368-1144.
gxa15{at}po.cwru.edu; cobalt55{at}usa.net
Ann. N.Y. Acad. Sci. 977: 45-64 (2002).
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 (AßPP).
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.
