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Inhibition of APP Trafficking by Tau Protein Does Not Increase the Generation of Amyloid‐β Peptides
Author(s) -
Goldsbury Claire,
Mocanu MariaMagdalena,
Thies Edda,
Kaether Christoph,
Haass Christian,
Keller Patrick,
Biernat Jacek,
Mandelkow Eckhard,
Mandelkow EvaMaria
Publication year - 2006
Publication title -
traffic
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.677
H-Index - 130
eISSN - 1600-0854
pISSN - 1398-9219
DOI - 10.1111/j.1600-0854.2006.00434.x
Subject(s) - vesicle , amyloid precursor protein , axoplasmic transport , microbiology and biotechnology , amyloid precursor protein secretase , neurite , biology , transfection , axon , vesicular transport protein , microtubule , synaptic vesicle , alpha secretase , endosome , microtubule associated protein , biophysics , intracellular , biochemistry , alzheimer's disease , in vitro , medicine , disease , membrane , gene
Amyloid‐β, 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‐β 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 β‐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‐β levels. In singly transfected axons, APP‐YFP was transported in large tubules and vesicles moving very fast (on average 3 µm/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 2× slower (on average 1.6 µm/s) with ~18× 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‐β is not generated in transit when transport is blocked by tau.