APOE4 dysregulates autophagy in cultured cells

Abstract

Human APOE4 (apolipoprotein E4 isoform) is a powerful genetic risk factor for late-onset Alzheimer disease (AD). Many groups have investigated the effect of APOE4 on the degradation of amyloid β (Aβ), the main component of plaques found in the brains of AD patients. However, few studies have focused on the degradation of APOE itself. We investigated the lysosomal trafficking of APOE in cells and found that APOE from the post-Golgi compartment is degraded through an autophagic process requiring the lysosomal membrane protein LAMP2A. We found that APOE4 accumulates in enlarged lysosomes, alters autophagic flux, and changes the proteomic contents of lysosomes following internalization. This dysregulated lysosomal trafficking may represent one of the mechanisms that contributes to AD pathogenesis.

Keywords: APOE; APOE4; Alzheimer’s disease; LAMP2A; chaperone-mediated autophagy.

Figure 1.

Aberrant lysosomal trafficking of APOE4 (below, orange) vs. APOE3 (above, blue). APOE is trafficked to the lysosome from the post-Golgi compartment, and accumulates in late endosomes and lysosomes. APOE4 perturbs autophagic flux, causes an accumulation of LC3-II and prevents mitochondrial proteins from reaching the lysosome.

Figure 2.

APOE is degraded by LAMP2A-dependent autophagy. (A) LAMP2A may participate in microautophagy of secretory vesicles containing APOE. (B) APOE may escape secretory vesicles into the cytoplasm, where it can be recognized by HSPA8/HSC70, which then binds to LAMP2A. LAMP2A forms a multimer on the lysosomal surface and facilitates the transfer of APOE into the lysosomal lumen by CMA. (C) LAMP2A also functions in autophagosomal fusion. APOE is degraded by macroautophagy; however, knockdown of LAMP2A has an additive effect with knockdown of other macroautophagy proteins, making it more likely that multiple separate autophagic processes are contributing to degradation of APOE.