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PTK2B affects the levels of Aβ in blood and brain and behavioral functions via targeting LRP-1 transporter in Aβ-induced cognitive dysfunction mice

HAO Kai-Min, LIU Zhen, WANG Hao-Yu, LI Kun, QI Wen-Xiu^*

Fenyang College of Shanxi Medical University, Fenyang 032200, China

Abstract

The aim of the present study was to explore the correlation between ptk2b/PTK2B (protein tyrosine kinase 2 beta, a ptk2b-encoded protein) and the level of low density lipoprotein receptor-related protein-1 (LRP-1), as well as to uncover the relationship between the changes in beta amyloid protein (Aβ) levels in blood and brain and the expression of ptk2b in Aβ-induced cognitive dysfunction mice. A total of 64 3-month-old C57BL/6J mice were divided randomly into the experimental group and control group. All mice underwent the intracerebroventricular (i.c.v.) intubation. Mice in the experimental group received the i.c.v. infusion of oligomeric Aβ1-42 (0.1 μg/μL, 3.6 μL) to construct the cognitively impaired models, and three days later, those mice were further injected with PF431396 (an inhibitor of PTK2B, 15 μg/mL, Aβ + PF group), phorbol-12-myristate-13-acetate (PMA, an agonist of PTK2B, 18.75 μg/mL, Aβ + PMA group), RAP (an inhibitor of LRP-1, 0.2 μg/mL, Aβ + RAP group) or normal saline (Aβ + NS group). For mice in the control group, they underwent the i.c.v. infusion of NS, and 3 days later, they were additionally injected with PF431396 (PF group), PMA (PMA group), RAP (RAP group) or NS (NS group) in the volume of 2 μL. One week later, all mice were subjected to the determination of behavioral function in Morris water maze and the measurement of expression of Aβ1-42, LRP-1 and PTK2B in blood and hippocampus using immunohistochemistry (IHC) staining, enzyme-linked immunosorbent assay (ELISA) and Western blot, and the measurement of mRNA expression of ptk2b in hippocampus using qRT-PCR. The results showed that the infusion of Aβ induced an increase of Aβ1-42 level in hippocampus and a decrease in blood, with the down-regulation of LRP-1 protein expression in hippocampus and up-regulation of mRNA and protein expression of ptk2b in hippocampus. For cognitively impaired mice, intervention of PF431396 caused the down-regulation of protein and mRNA expression of ptk2b in the hippocampus, while LRP-1 in hippocampus was up-regulated with a decrease in the level of Aβ1-42 in hippocampus and an increase in the level of Aβ1-42 in the blood, as well as significant improvement in cognitive function, while the administration of PMA resulted in the opposite changes. Moreover, the administration of RAP triggered the down-regulation of LRP-1 expression in hippocampus and an increase in the level of Aβ1-42 in hippocampus and a decrease in the level of Aβ1-42 in blood, with the deterioration of the behavioral functions, while protein and mRNA expression of ptk2b in hippocampus showed no evident changes. These results suggest that, in cognitively impaired mice, PTK2B, possibly via down-regulating LRP-1, increases the Aβ1-42 level in brain, but decreases the Aβ1-42 level in blood, thereby deteriorating the cognitive and behavioral functions of mice.

Key words: Alzheimer’s disease; beta amyloid protein; low density lipoprotein receptor-related protein-1; PTK2B; C57BL/6J mice

Received: 2020-10-09　　Accepted: 2021-01-25

Corresponding author: 祁文秀　　E-mail: fycqwx@163.com

DOI: 10.13294/j.aps.2021.0069

Citing This Article：

HAO Kai-Min, LIU Zhen, WANG Hao-Yu, LI Kun, QI Wen-Xiu. PTK2B affects the levels of Aβ in blood and brain and behavioral functions via targeting LRP-1 transporter in Aβ-induced cognitive dysfunction mice. Acta Physiol Sin 2021; 73 (5): 845-854 (in Chinese with English abstract).