Phosphorylation-state dependent intraneuronal sorting of A differentially impairs autophagy and the endo-lysosomal system

Progressive accumulation of amyloid-beta (A beta) aggregates in extracellular plaques is a characteristic hallmark of Alzheimer disease (AD). A beta is also found in intraneuronal deposits and associated with alterations of the endo-lysosomal system and impairment of macroautophagy/autophagy. Here, we assessed the effect of A beta phosphorylation on neuronal autophagy and the endo-lysosomal pathway. Analysis of APP-PSEN1dE9 transgenic mice revealed a phosphorylation-state dependent intraneuronal accumulation of A beta species in endo-lysosomal and autophagy-related compartments. Cell biological studies further demonstrate a differential uptake and sorting of phosphorylated A beta variants in cultured neurons, and phosphorylation-state specific effects of A beta variants on neuronal autophagy and lysosomal function. While A beta phosphorylated at serine residue 8 accumulated in autophagosomes, A beta phosphorylated at serine residue 26 showed efficient transport to lysosomes. The selective sorting of phosphorylated A beta species caused differential impairment of vesicular transport and lysosomal function associated with neurotoxicity. Thus, the relative occurrence of phosphorylated A beta species and their intraneuronal accumulation could contribute to AD pathogenesis, and to the commonly observed aberrations of the vesicular transport system already at the early stages of the disease.