UV Accelerates Amyloid Precursor Protein (APP) Processing and Disrupts APP Axonal Transport

ALMENAR-QUERALT A; FALZONE T; SHEN T; ARREOLA M; NEIRDERST T; KIM C; WILLIAMS D; GOLDSTEIN L

JOURNAL OF NEUROSCIENCE

SOC NEUROSCIENCE

Lugar: Washington; Año: 2014 vol. 34 p. 3320 - 3339

0270-6474

Overexpression and/or abnormal cleavage of amyloid precursor protein (APP) are linked to Alzheimer?s disease (AD) development andprogression. However, the molecular mechanisms regulating cellular levels of APP or its processing, and the physiological and pathologicalconsequences of altered processing are not well understood. Here, using mouse and human cells, we found that neuronal damageinduced by UV irradiation leads to specific APP, APLP1, and APLP2 decline by accelerating their secretase-dependent processing.Pharmacological inhibition of endosomal/lysosomal activity partially protects UV-induced APP processing implying contribution of theendosomal and/or lysosomal compartments in this process.Wefound that a biological consequence of UV-induced-secretase processingof APP is impairment of APP axonal transport. To probe the functional consequences of impaired APP axonal transport, we isolatedand analyzed presumptive APP-containing axonal transport vesicles from mouse cortical synaptosomes using electron microscopy,biochemical, and mass spectrometry analyses. We identified a population of morphologically heterogeneous organelles that containsAPP, the secretase machinery, molecular motors, and previously proposed and new residents of APP vesicles. These possible cargoes areenriched in proteins whose dysfunction could contribute to neuronal malfunction and diseases of the nervous system including AD.Together, these results suggest that damage-induced APP processing might impair APP axonal transport, which could result in failure ofsynaptic maintenance and neuronal dysfunction.