Involvement of receptor tyrosine kinase Tyro3 in amyloidogenic APP processing and β-amyloid deposition in Alzheimer's disease models.
Alzheimer's disease (AD) is the most common progressive neurodegenerative disease known to humankind. It is characterized by brain atrophy, extracellular amyloid plaques, and intracellular neurofibril tangles. β-Amyloid cascade is considered the major causative player in AD. Up until now, the mechanisms underlying the process of Aβ generation and accumulation in the brain have not been well understood. Tyro3 receptor belongs to the TAM receptor subfamily of receptor protein tyrosine kinases (RPTKs). It is specifically expressed in the neurons of the neocortex and hippocampus. In this study, we established a cell model stably expressing APPswe mutants and producing Aβ. We found that overexpression of Tyro3 receptor in the cell model significantly decreased Aβ generation and also down-regulated the expression of β-site amyloid precursor protein cleaving enzyme (BACE1). However, the effects of Tyro3 were inhibited by its natural ligand, Gas6, in a concentration-dependent manner. In order to confirm the role of Tyro3 in the progression of AD development, we generated an AD transgenic mouse model accompanied by Tyro3 knockdown. We observed a significant increase in the number of amyloid plaques in the hippocampus in the mouse model. More plaque-associated clusters of astroglia were also detected. The present study may help researchers determine the role of Tyro3 receptor in the neuropathology of AD.
Department of Physiology, Capital Medical University, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Beijing, People's Republic of China.
Yan
Y
Zheng
Qi
Q
Wang
Bing
B
Xiao
Qingjun
Q
Lu
Yizheng
Y
Wang
Xiaomin
X
Wang
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D015153:Blotting, Western; D004797:Enzyme-Linked Immunosorbent Assay; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000099255:Growth Arrest-Specific Protein 6
D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D016282:Aspartic Acid Endopeptidases; D036341:Intercellular Signaling Peptides and Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000099255:Growth Arrest-Specific Protein 6; C513478:Tyro3 protein, mouse; C509282:Bace1 protein, mouse