Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice.
Accumulating evidence strongly suggests that the AD brain is characterized by impairments in energy metabolism, and vascular hypoperfusion, whereby oxidative stress appears to be an especially important contributor to neuronal death and development of AD pathology. We hypothesized that mitochondria play a key role in the generation of reactive oxygen species, resulting in oxidative damage to neuronal cell bodies, as well as other cellular compartments in the AD brain. All of these changes have been found to accompany AD pathology. In this review we have outlined recent evidence from the literature and our own original studies concerning the role of mitochondrial abnormalities and vascular damage in the pathogenesis of AD and AD-like pathology in transgenic mice (as a model for human AD). We examined ultrastructural features of vascular lesions and mitochondria from vascular wall cells in human AD brain biopsies, in human short post-mortem brain tissues and in yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (A beta PP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5kb deleted and mouse mtDNA was performed along with immunocytochemistry using antibodies against amyloid beta precursor protein (A beta PP), 8-hydroxy-2'-guanosine (8OHG) and cytochrome C oxidase (COX) were studied at the electron microscopic levels. There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC and C57B6/SJL Tg(+) mice compared to aged-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 aged-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, 8OHG and COX in the same cellular compartment. Our observations first time demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress induced damage.
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002536:Cerebral Arteries / Q000473:pathology / Q000503:physiopathology; D002561:Cerebrovascular Disorders / Q000150:complications* / Q000473:pathology / Q000503:physiopathology*; D004272:DNA, Mitochondrial / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004195:Disease Models, Animal; D003576:Electron Transport Complex IV / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D018384:Oxidative Stress / Q000502:physiology*
D016564:Amyloid beta-Protein Precursor; D004272:DNA, Mitochondrial; D000080242:8-Hydroxy-2'-Deoxyguanosine; D003576:Electron Transport Complex IV; D003849:Deoxyguanosine