The cell biology of APOE in the brain

Abstract

Apolipoprotein E (APOE) traffics lipids in the central nervous system. The E4 variant of APOE is a major genetic risk factor for Alzheimer's disease (AD) and a multitude of other neurodegenerative diseases, yet the molecular mechanisms by which APOE4 drives disease are still unclear. A growing collection of studies in iPSC models, knock-in mice, and human postmortem brain tissue have demonstrated that APOE4 expression in astrocytes and microglia is associated with the accumulation of cytoplasmic lipid droplets, defects in endolysosomal trafficking, impaired mitochondrial metabolism, upregulation of innate immune pathways, and a transition into a reactive state. In this review, we collate these developments and suggest testable mechanistic hypotheses that could explain common APOE4 phenotypes.

Keywords: Alzheimer’s disease; apolipoprotein E; astrocytes; lipid droplets; lipoproteins; microglia.

Figure 1:. APOE-mediated intercellular lipid transport between astrocytes and neurons

Lipids synthesized in astrocytes are packaged into APOE-coated lipoprotein particles, secreted, and taken up by neurons for building membranes and synapses. Neurons secrete or efflux peroxidated lipids to APOE-lipoproteins, which are taken up by astrocytes for detoxification. Reactive astrocytes secrete lipoproteins with more saturated fatty acids that promote neuron death via lipoapoptosis.

Figure 2:. Trafficking of APOE

(a) Secreted APOE is translocated into the lumen of the endoplasmic reticulum during or after translation. APOE can also divert from translocation into the ER and instead target the surface of cytoplasmic LDs. (b) In the lumen of the ER, APOE protein forms into lipid-poor lipoproteins particles via an unknown mechanism and traffics to the Golgi. In the Golgi, APOE is glycosylated and secreted. (c) On the extracellular surface of the plasma membrane, nascent APOE-lipoproteins are lipidated by ABC transport proteins, primarily ABCA1. APOE also binds to heparan sulfate proteoglycans on the cell surface, which may help recruit them to ABC transporters for lipidation. (d) APOE on the surface of lipoproteins binds to cell surface APOE receptors, primarily LDLR and LRP1. This initiates receptor-mediated endocytosis of the receptor-APOE complex. (e) Lipoproteins traffic to the lysosome and the lipids contained within are transported out into the receiving cell. Multiple glial and neuronal cell types secrete and/or endocytose APOE.