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

OTERO, MARÍA GABRIELA; BESSONE, IVAN FERNANDEZ; HALLBERG, ALAN EARLE; CROMBERG, LUCAS ENEAS; DE ROSSI, MARÍA CECILIA; SAEZ, TRINIDAD M.; LEVI, VALERIA; ALMENAR-QUERALT, ANGELS; FALZONE, TOMÁS LUIS

JOURNAL OF CELL SCIENCE

COMPANY OF BIOLOGISTS LTD

Año: 2018

0021-9533

Alzheimer Disease (AD) pathology includes the accumulation of poly-ubiquitinated proteins and failures in proteasome-dependent degradation. Whereas the distribution of proteasomes and its role in synaptic function have been studied, whether proteasome activity regulates the axonal transport and metabolism of the amyloid precursor protein (APP), remains elusive. Using live imaging in primary hippocampal neurons, we showed that proteasome inhibition rapidly and severely impairs the axonal transport of APP. Fluorescent cross-correlation analyses and membrane internalization blockage showed that plasma membrane APP do not contribute to transport defects. Moreover, by western blots and double-color APP imaging we demonstrated that proteasome inhibition precludes APP axonal transport by enhancing its endo-lysosomal delivery where β-cleavage is induced. Together, we found that proteasomes controls the distal transport of APP and can re-distribute Golgi-derived vesicles to the endo-lysosomal pathway. This crosstalk between proteasomes and lysosomes regulates APP intracellular dynamics, and defects in proteasome activity can be considered a contributing factor that lead to abnormal APP metabolism in AD.