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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

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Abstract

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.

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Abbreviations

AD:

Alzheimer’s disease

APP:

amyloid precursor protein

BACE1:

β-secretase

Cx:

cortex

ECE-1:

endothelin-converting enzyme-1

IDE:

insulin-degrading enzyme

NEP:

neprilysin

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Acknowledgments

The authors are grateful to J. Bencatova, Z. Cetlova, and A. Kempna for help in conducting experiments.

Funding

Supported by grants FP7-PEOPLE-2010-IEF, MRC, ARUK, VEGA 1/0266/18 and partially by Russian Foundation for Basic Research (grant 19-015-00232) and Russian Federation state budget (assignment АААА-А18-118012290373-7).

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Correspondence to Natalia N. Nalivaeva.

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The authors declare no conflict of interests in financial or any other sphere. All applicable international, national, and/or institutional guidelines for the care and use of animals were followed.

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Babusikova, E., Dobrota, D., Turner, A.J. et al. 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. Biochemistry Moscow 86, 680–692 (2021). https://doi.org/10.1134/S0006297921060067

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