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

Abstract

Overexpression and/or abnormal cleavage of amyloid precursor protein (APP) are linked to Alzheimer's disease (AD) development and progression. However, the molecular mechanisms regulating cellular levels of APP or its processing, and the physiological and pathological consequences of altered processing are not well understood. Here, using mouse and human cells, we found that neuronal damage induced 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 the endosomal and/or lysosomal compartments in this process. We found that a biological consequence of UV-induced ␥-secretase processing of APP is impairment of APP axonal transport. To probe the functional consequences of impaired APP axonal transport, we isolated and 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 contains APP, the secretase machinery, molecular motors, and previously proposed and new residents of APP vesicles. These possible cargoes are enriched 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 of synaptic maintenance and neuronal dysfunction.

Fe65 Ser228 is phosphorylated by ATM/ATR and inhibits Fe65–APP-mediated gene transcription

“…These findings are in agreement with previous studies showing down-regulation of APP in response to both UV and camptothecin, though different mechanisms were proposed, with Cuesta et al [28] suggesting a p53-dependent reduction in the transcription of APP, whereas Almenar-Queralt et al [29] showed that the decrease in APP was due to secretase-mediated cleavage [28][29][30]. It is unclear whether loss of the Fe65-APP complex preceded the depletion of APP in cells or vice versa.…”

Cellular Functions of the Amyloid Precursor Protein from Development to Dementia

“…Both b-and g-secretase can be found in axons and somatodendritic compartments (DeBoer et al, 2014;Sannerud et al, 2011), and both can be found in vesicles that also contain APP and kinesin-1 (Almenar-Queralt et al, 2014;Kamal et al, 2001). Co-localization of these components in the somatodendritic compartment may be regulated by synaptic activity (Das et al, 2013).…”

Bidirectional cargo transport: moving beyond tug of war

“…Axons and dendrites contain a diverse array of bidirectionally transported vesicles, generally ranging in size from a few tens to a few hundred nanometers. These include secretory vesicles 25–27 , lysosomal vesicles 7, 28 , autophagosomes 29 , and vesicles containing amyloid precursor protein (APP) 30–32 and mammalian prion protein 8 . Transport of these diverse neuronal cargo involves different motors, adaptors, and regulatory proteins, but in general, similar conceptual models have been applied to understanding the molecular mechanisms underlying bidirectional transport.…”