Apolipoprotein E intersects with amyloid-β within neurons

Abstract

Apolipoprotein E4 (ApoE4) is the most important genetic risk factor for Alzheimer's disease (AD). Among the earliest changes in AD is endosomal enlargement in neurons, which was reported as enhanced in ApoE4 carriers. ApoE is thought to be internalized into endosomes of neurons, while β-amyloid (Aβ) accumulates within neuronal endosomes early in AD. However, it remains unknown whether ApoE and Aβ intersect intracellularly. We show that internalized astrocytic ApoE localizes mostly to lysosomes in neuroblastoma cells and astrocytes, while in neurons it preferentially localizes to endosomes–autophagosomes of neurites. In AD transgenic neurons, astrocyte-derived ApoE intersects intracellularly with amyloid precursor protein (APP)/Aβ. Moreover, ApoE4 increases the levels of endogenous and internalized Aβ42 in neurons. Taken together, we demonstrate differential localization of ApoE in neurons, astrocytes and neuron-like cells, and show that internalized ApoE intersects with APP/Aβ in neurons, which may be of considerable relevance to AD.