Is Alzheimer's disease a mitochondrial disorder?
Cell bodies of neurons at risk of death in Alzheimer's disease (AD) have increased lipid peroxidation, nitration, free carbonyls, and nucleic acid oxidation. These oxidative changes occur in all vulnerable neurons and are reduced in neurons that contain neurofibrillary pathology. In this review, the authors provide a summary of recent work that demonstrates key abnormalities that may play a part in initiating and promoting neuronal oxidative damage. Mitochondrial abnormalities are clearly involved as a source of reactive oxygen species that culminates in perikaryal oxidative damage. However, because mitochondria in AD do not exhibit striking evidence of oxidative damage, as would be expected if they produced free radicals directly, the authors suspected that abnormal mitochondria are responsible for supplying a key reactant, that once in the cytoplasm, releases radicals. Because abnormal mitochondria, H2O2 and redox-active iron are juxtaposed in the same AD neuron, it has all the markings of a "radical factory." The proximal causes of mitochondrial abnormalities likely involve reentry into the cell cycle, where organellokinesis and proliferation results in an increase of mitochondria and intermediately differentiated cells, with a consequent increase in turnover. Supporting this, the authors have considerable in vivo and in vitro evidence for mitotic disturbances in AD.
Cash
Adam D
AD
Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Perry
George
G
Ogawa
Osamu
O
Raina
Arun K
AK
Zhu
Xiongwei
X
Smith
Mark A
MA
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D002453:Cell Cycle; D005609:Free Radicals / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress
D005609:Free Radicals