amyloid precursor protein (app) mediated regulation of ganglioside homeostasis linking alzheimers disease pathology with ganglioside metabolism淀粉样前体蛋白(app)介导的神经节苷脂调节体内平衡连接阿尔茨海默病病理和神经节苷脂代谢.pdfVIP

Amyloid Precursor Protein (APP) Mediated Regulation of Ganglioside Homeostasis Linking Alzheimer’s Disease Pathology with Ganglioside Metabolism 1,2,3 3 ¨ 3 ¨ 3 3 Marcus O. W. Grimm *, Eva G. Zinser , Sven Grosgen , Benjamin Hundsdorfer , Tatjana L. Rothhaar , 3 4 5 4 ¨ 6 3 Verena K. Burg , Lars Kaestner , Thomas A. Bayer , Peter Lipp , Ulrike Muller , Heike S. Grimm , Tobias Hartmann1,2,3* ¨ ¨ 1 Deutsches Institut fur DemenzPravention (DIDP), Saarland University, Homburg/Saar, Germany, 2 Neurodegeneration and Neurobiology, Saarland University, Homburg/ Saar, Germany, 3 Experimental Neurology, Saarland University, Homburg/Saar, Germany, 4 Molecular Cellbiology, Saarland University, Homburg/Saar, Germany, 5 Department for Psychiatry, University of Goettingen, Goettingen, Germany, 6 Institute for Pharmacy and Molecular Biotechnology (IPMB), University of Heidelberg, Heidelberg, Germany Abstract Gangliosides are important players for controlling neuronal function and are directly involved in AD pathology. They are among the most potent stimulators of Ab production, are enriched in amyloid plaques and bind amyloid beta (Ab). However, the molecular mechanisms linking gangliosides with AD are unknown. Here we identified the previously unknown function of the amyloid precursor protein (APP), specifically its cleavage products Ab and the APP intracellular domain (AICD), of regulating GD3-synthase (GD3S). Since GD3S is the key enzyme converting a- to b-series gangliosides, it therefore plays a major rol