Defective Transcytosis of APP and Lipoproteins in human iPSC-derived neurons with Familial Alzheimer’s Disease Mutations
| Autor: | Elizabeth A. Roberts, Jessica E. Young, Mariah Dunlap, Lawrence S.B. Goldstein, Sol M. Reyna, Rik van der Kant, Grace Woodruff, Julia A. Callender |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
PS1 Mutant Endocytic cycle Induced Pluripotent Stem Cells Endocytic recycling GTPase Biology Endocytosis General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Amyloid beta-Protein Precursor Alzheimer Disease medicine Presenilin-1 endocytosis Humans RNA Messenger Axon lcsh:QH301-705.5 Neurons iPSC FAD Phenotype Axons Cell biology Lipoproteins LDL 030104 developmental biology medicine.anatomical_structure Biochemistry Transcytosis lcsh:Biology (General) nervous system rab GTP-Binding Proteins Mutation lipids (amino acids peptides and proteins) Amyloid Precursor Protein Secretases APP Alzheimer’s disease Low Density Lipoprotein Receptor-Related Protein-1 |
| Zdroj: | Cell Reports, Vol 17, Iss 3, Pp 759-773 (2016) |
| Popis: | We investigated early phenotypes caused by familial Alzheimer’s Disease (fAD) mutations in isogenic human iPSC-derived neurons. Analysis of neurons carrying fAD PS1 or APP mutations introduced using genome editing technology at the endogenous loci revealed that fAD mutant neurons had previously unreported defects in the recycling state of endocytosis and soma-to-axon transcytosis of APP and lipoproteins. The endocytosis reduction could be rescued through treatment with a β-secretase inhibitor. Our data suggest that accumulation of β-CTF fragments of APP, but not Aβ, slow vesicle formation from an endocytic recycling compartment marked by the transcytotic GTPase Rab11. We confirm previous results that endocytosis is affected in AD, and extend these to uncover a neuron-specific defect. Decreased lipoprotein endocytosis and transcytosis to the axon suggests that a neuron-specific impairment in endocytic axonal delivery of lipoproteins and other key materials might compromise synaptic maintenance in fAD. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|