Mitochondrial ATP-synthase in the entorhinal cortex is a target of oxidative stress at stages I/II of Alzheimer's disease pathology.
Oxidative stress has been implicated in the pathogenesis of several neurodegenerative diseases including Alzheimer's disease (AD). Several proteins have been identified as targets of oxidative damage in AD dementia (usually stages V/VI of Braak) and in subjects with mild cognitive impairment associated with middle stages of AD pathology (stage IV of Braak). In this study, we investigate whether brain proteins are locally modified by oxidative stress at the first stages of AD-related pathology when morphological lesions are restricted to the entorhinal and transentorhinal cortices of neurofibrillary pathology (stages I/II of Braak). Using a proteomic approach, we show that the alpha subunit of the mitochondrial adenosine triphosphate (ATP)-synthase is distinctly lipoxidized in the entorhinal cortex at Braak stages I/II compared with age-matched controls. In addition, ATP-synthase activity is significantly lower in Braak stages I/II than age-matched control, while electron transport chain, expressed by the mitochondrial complex I activity, remains not affected. This is the first study showing oxidative damage in the first stage, and clinically silent period, of AD-related pathology characterized by entorhinal and transentorhinal tauopathy.
Terni
Beatrice
B
Institut de Neuropatologia, Servei Anatomia Patològica, IDIBELL, Hospital Universitari de Bellvitge, Universitat de Barcelona, CIBERNED, Hospitalet de Llobregat, Barcelona, Spain.
Boada
Jordi
J
Portero-Otin
Manuel
M
Pamplona
Reinald
R
Ferrer
Isidro
I
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000368:Aged; D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology; D015153:Blotting, Western; D001894:Borohydrides; D002352:Carrier Proteins / Q000378:metabolism; D018450:Disease Progression; D015180:Electrophoresis, Gel, Two-Dimensional; D018728:Entorhinal Cortex / Q000201:enzymology* / Q000473:pathology; D005260:Female; D019085:Fluorescent Antibody Technique, Direct; D006801:Humans; D006868:Hydrolysis; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D013058:Mass Spectrometry; D008565:Membrane Proteins / Q000378:metabolism; D018613:Microscopy, Confocal; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology*; D025261:Mitochondrial Proton-Translocating ATPases / Q000378:metabolism*; D016874:Neurofibrillary Tangles / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D014357:Trypsin
D001894:Borohydrides; D002352:Carrier Proteins; D008565:Membrane Proteins; C025364:sodium borohydride; D014357:Trypsin; D000251:Adenosine Triphosphatases; D025261:Mitochondrial Proton-Translocating ATPases; C020439:oligomycin sensitivity-conferring protein