| First Author | Gotoh N | Year | 2020 |
| Journal | J Biol Chem | Volume | 295 |
| Issue | 28 | Pages | 9650-9662 |
| PubMed ID | 32467230 | Mgi Jnum | J:297152 |
| Mgi Id | MGI:6466913 | Doi | 10.1074/jbc.RA119.012386 |
| Citation | Gotoh N, et al. (2020) Amyloidogenic processing of amyloid beta protein precursor (APP) is enhanced in the brains of alcadein alpha-deficient mice. J Biol Chem 295(28):9650-9662 |
| abstractText | Alzheimer's disease (AD) is a very common neurodegenerative disorder, chiefly caused by increased production of neurotoxic beta-amyloid (Abeta) peptide generated from proteolytic cleavage of beta-amyloid protein precursor (APP). Except for familial AD arising from mutations in the APP and presenilin (PSEN) genes, the molecular mechanisms regulating the amyloidogenic processing of APP are largely unclear. Alcadein alpha/calsyntenin1 (ALCalpha/CLSTN1) is a neuronal type I transmembrane protein that forms a complex with APP, mediated by the neuronal adaptor protein X11-like (X11L or MINT2). Formation of the ALCalpha-X11L-APP tripartite complex suppresses Abeta generation in vitro, and X11L-deficient mice exhibit enhanced amyloidogenic processing of endogenous APP. However, the role of ALCalpha in APP metabolism in vivo remains unclear. Here, by generating ALCalpha-deficient mice and using immunohistochemistry, immunoblotting, and co-immunoprecipitation analyses, we verified the role of ALCalpha in the suppression of amyloidogenic processing of endogenous APP in vivo We observed that ALCalpha deficiency attenuates the association of X11L with APP, significantly enhances amyloidogenic beta-site cleavage of APP, especially in endosomes, and increases the generation of endogenous Abeta in the brain. Furthermore, we noted amyloid plaque formation in the brains of human APP-transgenic mice in an ALCalpha-deficient background. These results unveil a potential role of ALCalpha in protecting cerebral neurons from Abeta-dependent pathogenicity in AD. |
