Mitochondrial dysfunction: an early event in Alzheimer pathology accumulates with age in AD transgenic mice.
Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer's disease integrating genetic factors related to enhanced amyloid-beta (Ass) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. To further clarify the synergistic effects of aging and Ass pathology, we used isolated mitochondria of double Swedish and London mutant APP transgenic mice and of non-tg littermates. Pronounced mitochondrial dysfunction in adult Thy-1 APP mice, such as a drop of mitochondrial membrane potential and reduced ATP-levels already appeared at 3 months when elevated intracellular but not extracellular Ass deposits are present. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species, an altered Bcl-xL/Bax ratio and reduction of COX IV activity. We observed significant decreases in state 3 respiration and FCCP-uncoupled respiration in non-tg mice after treatment with extracellular Ass. Similar deficits were seen only in aged Thy-1 APP mice, probably due to compensation within the respiratory chain in young animals. We conclude that Ass dependent mitochondrial dysfunction starts already at 3 months in this AD model before extracellular deposition of Ass and progression accelerates substantially with aging.
Hauptmann
S
S
Department of Pharmacology, ZAFES, Biocenter, University of Frankfurt, 60438 Frankfurt, Germany.
Scherping
I
I
Dröse
S
S
Brandt
U
U
Schulz
K L
KL
Jendrach
M
M
Leuner
K
K
Eckert
A
A
Müller
W E
WE
D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging; D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D001921:Brain / Q000503:physiopathology; D004195:Disease Models, Animal; D004579:Electron Transport / Q000502:physiology; D005260:Female; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000502:physiology*; D028361:Mitochondrial Diseases / Q000503:physiopathology*; D018384:Oxidative Stress / Q000502:physiology; D058255:Protease Nexins; D017382:Reactive Oxygen Species / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D051020:bcl-X Protein / Q000378:metabolism
C545487:APP protein, human; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; C494827:Bax protein, mouse; D058255:Protease Nexins; D017382:Reactive Oxygen Species; D011956:Receptors, Cell Surface; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D000255:Adenosine Triphosphate