title: Inhibition of APP trafficking by tau protein does not increase the generation of amyloid-beta peptides.
abstract: Amyloid-beta, a peptide derived from the precursor protein APP, accumulates in the brain and contributes to the neuropathology of Alzheimer's disease. Increased generation of amyloid-beta might be caused by axonal transport inhibition, via increased dwell time of APP vesicles and thereby higher probability of APP cleavage by secretase enzymes residing on the same vesicles. We tested this hypothesis using a neuronal cell culture model of inhibited axonal transport and by imaging vesicular transport of fluorescently tagged APP and beta-secretase (BACE1). Microtubule-associated tau protein blocks vesicle traffic by inhibiting the access of motor proteins to the microtubule tracks. In neurons co-transfected with CFP-tau, APP-YFP traffic into distal neurites was strongly reduced. However, this did not increase amyloid-beta levels. In singly transfected axons, APP-YFP was transported in large tubules and vesicles moving very fast (on average 3 microm/s) and with high fluxes in the anterograde direction (on average 8.4 vesicles/min). By contrast, BACE1-CFP movement was in smaller tubules and vesicles that were almost 2x slower (on average 1.6 microm/s) with approximately 18x lower fluxes (on average 0.5 vesicles/min). Two-colour microscopy of co-transfected axons confirmed that the two proteins were sorted into distinct carriers. The results do not support the above hypothesis. Instead, they indicate that APP is transported on vesicles distinct from the secretase components and that amyloid-beta is not generated in transit when transport is blocked by tau.
authors.affiliation: Max Planck Unit for Structural Molecular Biology, c/o DESY, Notkestrasse 85, 22607 Hamburg, Germany.
authors.forename: Claire
authors.initials: C
authors.lastname: Goldsbury
authors.forename: Maria-Magdalena
authors.initials: MM
authors.lastname: Mocanu
authors.forename: Edda
authors.initials: E
authors.lastname: Thies
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaether
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.forename: Patrick
authors.initials: P
authors.lastname: Keller
authors.forename: Jacek
authors.initials: J
authors.lastname: Biernat
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mandelkow
authors.forename: Eva-Maria
authors.initials: EM
authors.lastname: Mandelkow
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism; D002522:Chlorocebus aethiops; D005786:Gene Expression Regulation; D006801:Humans; D009474:Neurons / Q000378:metabolism; D010446:Peptide Fragments / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; D016875:tau Proteins