Accumulation of exogenous amyloid-beta peptide in hippocampal mitochondria causes their dysfunction: a protective role for melatonin.
Amyloid-beta (Aβ) pathology is related to mitochondrial dysfunction accompanied by energy reduction and an elevated production of reactive oxygen species (ROS). Monomers and oligomers of Aβ have been found inside mitochondria where they accumulate in a time-dependent manner as demonstrated in transgenic mice and in Alzheimer's disease (AD) brain. We hypothesize that the internalization of extracellular Aβ aggregates is the major cause of mitochondrial damage and here we report that following the injection of fibrillar Aβ into the hippocampus, there is severe axonal damage which is accompanied by the entrance of Aβ into the cell. Thereafter, Aβ appears in mitochondria where it is linked to alterations in the ionic gradient across the inner mitochondrial membrane. This effect is accompanied by disruption of subcellular structure, oxidative stress, and a significant reduction in both the respiratory control ratio and in the hydrolytic activity of ATPase. Orally administrated melatonin reduced oxidative stress, improved the mitochondrial respiratory control ratio, and ameliorated the energy imbalance.
Centro de Investigación Biomédica de Occidente del Instituto Mexicano del Seguro Social, Sierra Mojada 800 Colonia Independencia, 44340 Guadalajara, JAL, Mexico. rosalescorra@uthscsa.edu
Sergio
S
Rosales-Corral
Dario
D
Acuna-Castroviejo
Dun Xian
DX
Tan
Gabriela
G
López-Armas
José
J
Cruz-Ramos
Rubén
R
Munoz
Valery G
VG
Melnikov
Lucien C
LC
Manchester
Russel J
RJ
Reiter
D000251:Adenosine Triphosphatases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D019069:Cell Respiration / Q000187:drug effects; D002784:Cholesterol; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D006868:Hydrolysis / Q000187:drug effects; D007276:Injections, Intraventricular; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D008560:Membrane Fluidity / Q000187:drug effects; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D051336:Mitochondrial Membranes / Q000187:drug effects / Q000378:metabolism; D009410:Nerve Degeneration / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects; D020011:Protective Agents / Q000494:pharmacology*; D020836:Protein Structure, Quaternary; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species / Q000378:metabolism
D016229:Amyloid beta-Peptides; D020011:Protective Agents; D017382:Reactive Oxygen Species; D002784:Cholesterol; D000251:Adenosine Triphosphatases; D008550:Melatonin