Oxidative stress accelerates amyloid deposition and memory impairment in a double-transgenic mouse model of Alzheimer's disease.

Abstract

Oxidative stress is known to play a prominent role in the onset and early stage progression of Alzheimer's disease (AD). For example, protein oxidation and lipid peroxidation levels are increased in patients with mild cognitive impairment. Here, we created a double-transgenic mouse model of AD to explore the pathological and behavioral effects of oxidative stress. Double transgenic (APP/DAL) mice were constructed by crossing Tg2576 (APP) mice, which express a mutant form of human amyloid precursor protein (APP), with DAL mice expressing a dominant-negative mutant of mitochondrial aldehyde dehydrogenase 2 (ALDH2), in which oxidative stress is enhanced. Y-maze and object recognition tests were performed at 3 and 6 months of age to evaluate learning and memory. The accumulation of amyloid plaques, deposition of phosphorylated-tau protein, and number of astrocytes in the brain were assessed histopathologically at 3, 6, 9, and 12-15 months of age. The life span of APP/DAL mice was significantly shorter than that of APP or DAL mice. In addition, they showed accelerated amyloid deposition, tau phosphorylation, and gliosis. Furthermore, these mice showed impaired performance on Y-maze and object recognition tests at 3 months of age. These data suggest that oxidative stress accelerates cognitive dysfunction and pathological insults in the brain. APP/DAL mice could be a useful model for exploring new approaches to AD treatment.

• Authors: Takuya Kanamaru, Naomi Kamimura, Takashi Yokota, Katsuya Iuchi, Kiyomi Nishimaki, Shinya Takami, Hiroki Akashiba, Yoshitsugu Shitaka, Ken-Ichiro Katsura, Kazumi Kimura, Shigeo Ohta
• Journal: Neuroscience letters (Neurosci Lett) Vol. 587 Pg. 126-31 (Feb 05 2015) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 25529196 (Publication Type: Journal Article)
• Copyright: Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Amyloid
• Amyloid beta-Protein Precursor
• Mitochondrial Proteins
• tau Proteins
• ALDH2 protein, mouse
• Aldehyde Dehydrogenase
• Aldehyde Dehydrogenase, Mitochondrial

Topics

• Aldehyde Dehydrogenase (genetics)
• Aldehyde Dehydrogenase, Mitochondrial
• Alzheimer Disease (genetics, metabolism, psychology)
• Amyloid (metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Brain (metabolism)
• Gliosis
• Learning
• Memory Disorders (genetics, psychology)
• Mice, Transgenic
• Mitochondrial Proteins (genetics)
• Oxidative Stress
• Phosphorylation
• tau Proteins (metabolism)