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Involvement of receptor tyrosine kinase Tyro3 in amyloidogenic APP processing and β-amyloid deposition in Alzheimer's disease models.

Abstract

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.

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    • Authors

    Zheng Y, Wang Q, Xiao B, Lu Q, Wang Y, Wang X

    Institution

    Department of Physiology, Capital Medical University, Key Laboratory for Neurodegenerative Disorders of the Ministry of Education, Beijing, People's Republic of China.

    Source

    PloS one 7:6 2012 pg e39035

    MeSH

    Alzheimer Disease
    Amyloid Precursor Protein Secretases
    Amyloid beta-Peptides
    Amyloid beta-Protein Precursor
    Analysis of Variance
    Animals
    Aspartic Acid Endopeptidases
    Blotting, Western
    Enzyme-Linked Immunosorbent Assay
    Gene Knockdown Techniques
    HEK293 Cells
    Hippocampus
    Humans
    Immunohistochemistry
    Intercellular Signaling Peptides and Proteins
    Mice
    Mice, Transgenic
    Microscopy, Confocal
    Plaque, Amyloid
    Receptor Protein-Tyrosine Kinases

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22701746