Mitochondrial abnormalities in a streptozotocin-induced rat model of sporadic Alzheimer's disease.

Abstract

This study aimed to show that the rat model of sporadic Alzheimer's disease (sAD) generated by the intracerebroventricular (icv) injection of a sub-diabetogenic dose of streptozotocin (icvSTZ) is characterized by brain mitochondrial abnormalities. Three-month-old male Wistar rats were investigated 5 weeks after a single bilateral icv injection of STZ (3 mg/ Kg) or vehicle. icvSTZ administration induced a decrease in brain weight and cognitive decline, without affecting blood glucose levels. icvSTZ administration also resulted in a significant increase in hippocampal amyloid beta peptide 1-42 (Aβ(1-42)) levels as well as in cortical and hippocampal hyperphosphorylated tau protein levels. Brain mitochondria from icvSTZ rats revealed deficits in their function, as shown by a decrease in mitochondrial transmembrane potential, repolarization level, ATP content, respiratory state 3, respiratory control ratio and ADP/O index and an increase in lag phase of repolarization. Mitochondria from icvSTZ rats also displayed a decrease in pyruvate and α-ketoglutarate dehydrogenases and cytochrome c oxidase activities and an increase in the susceptibility to calcium-induced mitochondrial permeability transition. An increase in hydrogen peroxide and lipid peroxidation levels and a reduction in glutathione content were also observed in mitochondria from icvSTZ rats. These results demonstrate that the insulin-resistant brain state that characterizes this rat model of sAD is accompanied by the occurrence of mitochondrial abnormalities reinforcing the validity of this animal model to study sAD pathogenesis and potential therapies.

• Authors: Sónia C Correia, Renato X Santos, Maria S Santos, Gemma Casadesus, Joseph C Lamanna, George Perry, Mark A Smith, Paula I Moreira
• Journal: Current Alzheimer research (Curr Alzheimer Res) Vol. 10 Issue 4 Pg. 406-19 (May 01 2013) ISSN: 1875-5828 [Electronic] United Arab Emirates
• PMID: 23061885 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adenine Nucleotides
• Amyloid beta-Peptides
• Antibiotics, Antineoplastic
• Blood Glucose
• Malondialdehyde
• Streptozocin
• Hydrogen Peroxide
• Glutathione
• Glutathione Disulfide

Topics

• Adenine Nucleotides (metabolism)
• Alzheimer Disease (blood, chemically induced, pathology)
• Amyloid beta-Peptides (metabolism)
• Animals
• Antibiotics, Antineoplastic (toxicity)
• Blood Glucose
• Brain (drug effects, metabolism, pathology, ultrastructure)
• Disease Models, Animal
• Escape Reaction (drug effects)
• Glutathione
• Glutathione Disulfide (metabolism)
• Hydrogen Peroxide (metabolism)
• Male
• Malondialdehyde (metabolism)
• Maze Learning (drug effects, physiology)
• Membrane Potential, Mitochondrial (drug effects, physiology)
• Microscopy, Electron, Transmission
• Mitochondria (drug effects, metabolism, pathology)
• Oxygen Consumption
• Rats
• Rats, Wistar
• Reaction Time
• Streptozocin (toxicity)