Atherosclerotic lesions and mitochondria DNA deletions in brain microvessels: implication in the pathogenesis of Alzheimer's disease.
The pathogenesis that is primarily responsible for Alzheimer's disease (AD) and cerebrovascular accidents (CVA) appears to involve chronic hypoperfusion. We studied the ultrastructural features of vascular lesions and mitochondria in brain vascular wall cells from human AD biopsy samples and two transgenic mouse models of AD, yeast artificial chromosome (YAC) and C57B6/SJL Tg (+), which overexpress human amyloid beta precursor protein (AbetaPP). In situ hybridization using probes for normal and 5 kb deleted human and mouse mitochondrial DNA (mtDNA) was performed along with immunocytochemistry using antibodies against the Abeta peptide processed from AbetaPP, 8-hydroxy-2'-guanosine (8OHG), and cytochrome c oxidase (COX). More amyloid deposition, oxidative stress markers as well as mitochondrial DNA deletions and structural abnormalities were present in the vascular walls of the human AD samples and the AbetaPP-YAC and C57B6/SJL Tg (+) transgenic mice compared to age-matched controls. Ultrastructural damage in perivascular cells highly correlated with endothelial lesions in all samples. Therefore, pharmacological interventions, directed at correcting the chronic hypoperfusion state, may change the natural course of the development of dementing neurodegeneration.
Aliev
Gjumrakch
G
Department of Biology, University of Texas at San Antonio, San Antonio, Texas 78249-1664, USA. gjumrakch.aliev@utsa.edu
Gasimov
Eldar
E
Obrenovich
Mark E
ME
Fischbach
Kathryn
K
Shenk
Justin C
JC
Smith
Mark A
MA
Perry
George
G
D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D050197:Atherosclerosis; D001921:Brain / Q000098:blood supply* / Q000648:ultrastructure*; D004272:DNA, Mitochondrial / Q000648:ultrastructure*; D004195:Disease Models, Animal; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008833:Microcirculation; D009474:Neurons / Q000648:ultrastructure
D004272:DNA, Mitochondrial