Defective Transcytosis of APP and Lipoproteins in Human iPSC-Derived Neurons with Familial Alzheimer’s Disease Mutations

• DOI: 10.1016/j.celrep.2016.09.034
• Publication Date: 2016-10-11T16:00:55Z
• Authors: Grace Woodruff; Sol M. Reyna; Mariah Dunlap; Rik Van Der Kant; Julia A. Callender; Jessica E. Young; Elizabeth A. Roberts; Lawrence S.B. Gol...
• Keywords: Transcytosis

Highlights•FAD mutations impair endocytosis and transcytosis of APP lipoproteins•Reduced lipoprotein are rescued by β-secretase inhibitionSummaryWe investigated early phenotypes caused familial Alzheimer's disease (fAD) in isogenic human iPSC-derived neurons. Analysis neurons carrying fAD PS1 or introduced using genome editing technology at the endogenous loci revealed that mutant had previously unreported defects recycling state soma-to-axon lipoproteins. The reduction could be through treatment with a inhibitor. Our data suggest accumulation β-CTFs APP, but not Aβ, slow vesicle formation from an endocytic compartment marked transcytotic GTPase Rab11. We confirm previous results is affected AD extend these to uncover neuron-specific defect. Decreased axon impairment axonal delivery lipoproteins other key materials might compromise synaptic maintenance fAD.Graphical abstract