Lipoproteins are complexes of carrier proteins and lipids, including cholesterol, that in the cardiovascular and digestive systems are involved in the trafficking of dietary lipids. Apolipoprotein E is a component of lipoproteins and mediates the uptake of these lipoprotein particles into target tissues. In the liver, ApoE is incorporated into very low density lipopro-teins (VLDLs), which carry triglycerides and cholesterol to peripheral tissues, mainly muscle and adipose tissue. In the gut, ApoE becomes a component of chy-lomicrons and mediates the transport of dietary fat to the liver. In macrophages, the scavenger cells of the immune system, ApoE is involved in the resecretion of absorbed cholesterol. However, ApoE is also expressed in cells of the nervous system, predominantly in astrocytes. The role of ApoE secretion and its binding to the ApoE receptors (ApoERs) that are present on the surface of neurons is unclear at this point.
ApoE occurs in three major isoforms in the general human population, ApoE2, ApoE3, and ApoE4. As described earlier, the ApoE4 isoform, also known as ApoE e4, is associated with AD.
There are a variety of ApoE receptors that are expressed on the surface of neurons that may be involved in the pathological process by which ApoE contributes to AD. Two members of this neuronal family of ApoE receptors warrant particular attention: the very low density lipoprotein receptor (VLDLR) and the Apolipoprotein E receptor 2 (ApoER2). Both receptors participate in neuronal signaling pathways related to memory formation. These receptors bind not only ApoE but also the signaling molecule Reelin, a large protein of approximately 400 kDa that is secreted by interneurons dispersed throughout the neocortex and the hippocampus.
The ApoE/Reelin receptors ApoER2 and VLDLR couple to the adaptor protein Dab1, which is essential to ApoE/Reelin signaling. As I mentioned in Chapter 6, these receptors couple via Dab1 to the src pathway and potentially via this mechanism contribute to NMDA receptor regulation.
In a recent series of experiments, we found that mice lacking the ApoE/Reelin receptors VLDLR and ApoER2 have pronounced defects in memory formation and hippocampal long-term potentiation (69). Furthermore, Reelin greatly enhances LTP in hippocampal slices. Our results thus reveal a role for ApoE receptors in synaptic function and in the formation of long-term memory. These data are also consistent with a hypothetical model in which the promotion of memory dysfunction by ApoE4 might involve an impairment of this ApoE receptor-dependent signaling pathway—how this might be involved in AD is a current line of investigation in several laboratories.
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