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Effect of Global Brain Ischemia on Amyloid Precursor Protein Metabolism and Expression of Amyloid-Degrading Enzymes in Rat Cortex: Role in Pathogenesis of Alzheimer’s Disease

Eva Babusikova1,a, Dusan Dobrota1,b, Anthony J. Turner2,c, and Natalia N. Nalivaeva2,3,d*

1Comenius University in Bratislava, Jessenius Faculty of Medicine in Martin, Department of Medical Biochemistry, 036 01 Martin, Slovakia

2School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, LS2 9JT United Kingdom

3Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, 194223 St. Petersburg, Russia

* To whom correspondence should be addressed.

Received February 8, 2021; Revised April 20, 2021; Accepted April 20, 2021
The incidence of Alzheimer’s disease (AD) increases significantly following chronic stress and brain ischemia which, over the years, cause accumulation of toxic amyloid species and brain damage. The effects of global 15-min ischemia and 120-min reperfusion on the levels of expression of the amyloid precursor protein (APP) and its processing were investigated in the brain cortex (Cx) of male Wistar rats. Additionally, the levels of expression of the amyloid-degrading enzymes neprilysin (NEP), endothelin-converting enzyme-1 (ECE-1), and insulin-degrading enzyme (IDE), as well as of some markers of oxidative damage were assessed. It was shown that the APP mRNA and protein levels in the rat Cx were significantly increased after the ischemic insult. Protein levels of the soluble APP fragments, especially of sAPPβ produced by β-secretase, (BACE-1) and the levels of BACE-1 mRNA and protein expression itself were also increased after ischemia. The protein levels of APP and BACE-1 in the Cx returned to the control values after 120-min reperfusion. The levels of NEP and ECE-1 mRNA also decreased after ischemia, which correlated with the decreased protein levels of these enzymes. However, we have not observed any changes in the protein levels of insulin-degrading enzyme. Contents of the markers of oxidative damage (di-tyrosine and lysine conjugates with lipid peroxidation products) were also increased after ischemia. The obtained data suggest that ischemia shifts APP processing towards the amyloidogenic β-secretase pathway and accumulation of the neurotoxic Aβ peptide as well as triggers oxidative stress in the cells. These results are discussed in the context of the role of stress and ischemia in initiation and progression of AD.
KEY WORDS: Alzheimer’s disease (AD), amyloid precursor protein (APP), β-secretase (BACE-1), endothelin-converting enzyme-1 (ECE-1), global brain ischemia, insulin-degrading enzyme (IDE), neprilysin (NEP), stress

DOI: 10.1134/S0006297921060067