Proteasome stress leads to APP axonal transport defects by promoting its amyloidogenic processing in lysosomes

OTERO, MG; BESSONE, I; HALLBERG, A; CROMBERG, L; DE ROSSI, MC; SAEZ, T; LEVI, V; ALMENAR, A; FALZONE, T

JOURNAL OF CELL SCIENCE

COMPANY OF BIOLOGISTS LTD

Lugar: Cambridge; Año: 2018

0021-9533

Alzheimer disease (AD) pathology includes the accumulation ofpoly-ubiquitylated (also known as poly-ubiquitinated) proteins andfailures in proteasome-dependent degradation. Whereas thedistribution of proteasomes and its role in synaptic function havebeen studied, whether proteasome activity regulates the axonaltransport and metabolism of the amyloid precursor protein (APP),remains elusive. By using live imaging in primary hippocampalneurons, we showed that proteasome inhibition rapidly and severelyimpairs the axonal transport of APP. Fluorescence cross-correlationanalyses andmembrane internalization blockage experiments showedthat plasma membrane APP does not contribute to transport defects.Moreover, by western blotting and double-color APP imaging, wedemonstrated that proteasome inhibition precludes APP axonaltransport by enhancing its endo-lysosomal delivery, where β-cleavage is induced. Taken together, we found that proteasomescontrol the distal transport of APP and can re-distribute Golgi-derivedvesicles to the endo-lysosomal pathway. This crosstalk betweenproteasomes and lysosomes regulates the intracellular APP dynamics,and defects in proteasome activity can be considered a contributingfactor that leads to abnormal APP metabolism in AD.