Drug Discovery Opinion

ApoE is a lipid transport protein with roles in transport of dietary lipids, regulation of plasma cholesterol, and protection from atherosclerosis. In humans, there are three variants of ApoE (ApoE2, ApoE3 and ApoE4) and one of these, ApoE4, has been linked to earlier onset of Alzheimer’s disease. The mechanisms underlying the increased risk of Alzheimer’s disease remain unclear but researchers at UT Southwestern Medical Center have now shown that the ApoE4 variant reduces surface expression of receptors involved in synaptic plasticity by sequestering the receptors inside the cell.

ApoE interacts with members of the LDL receptor family and one of the receptors for ApoE, Apoer2, also acts as a signalling receptor for reelin, a protein that is important in the developing brain but also enhances NMDA receptor activity and increases long-term potentiation (LTP) in the adult brain. ApoE4 was found to reduce surface expression of NMDA and AMPA receptors as well as Apoer2 receptors, thereby impairing glutamatergic neurotransmission. β-Amyloid peptide, a hallmark of Alzheimer’s disease, suppresses LTP and the ability of reelin to counter the effects of β-amyloid peptide was almost completely abolished in mice expressing human ApoE4. The team are now trying to understand whether it is possible to build on their findings to develop new treatments for Alzheimer’s disease.

The study is published in the Proceedings of the National Academy of Sciences.

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