ApoE Receptors in the Brain: Novel Signaling Pathways with Potential Relevance for Alzheimer’s Disease
Apolipoprotein E (ApoE) is an intrinsic component of lipoproteins and is known to transport cholesterol and other lipids through the circulation and between cells. ApoE binds to a family of cell surface receptors, the LDL receptor gene family. This class of endocytic receptors mediates the internalization of the lipoprotein particle, followed by transport of the lipids to the lysosomes. Several years ago, one isoform of ApoE, ApoE4, was reported to be genetically associated with late-onset Alzheimer’s disease. The biochemical mechanism by which ApoE4 predisposes its carriers to this debilitating neurodegenerative condition remains largely an enigma. We have investigated whether ApoE receptors on neurons are involved in the molecular pathogenic process. LRP, a member of the LDL receptor gene family, binds the amyloid precursor protein (APP) on its extracellular domain and is also connected to the cytoplasmic tail of APP by the adaptor protein FE65. This two-point interaction suggests that LRP may affect the subcellular localization, routing, and possibly processing of APP. Recently, we also described a novel signaling pathway by which two other members of the family, the VLDL receptor and the ApoE receptor 2, serve to transmit a positional cue across the membrane to migrating neurons. The signaling molecule, Reelin, binds to the receptor ectodomains and induces tyrosine phosphorylation of the intracellular adaptor protein Disabled-1. Disruption of this ApoE receptor-mediated signal transduction pathway results in hyperphosphorylation of the microtubule stabilizing protein tau, a prerequisite for the formation of neurofibrillary tangles in humans afflicted with Alzheimer’s disease. These findings tie neuronal ApoE receptors directly to two of the prominent pathological changes that are diagnostic for the disease: amyloid plaques, caused by abnormal processing of APP, and neurofibrillary tangles, caused by hyperphosphorylation of tau. We conclude that ApoE receptors regulate essential cellular signaling pathways in neurons and that defects in these pathways may accelerate the onset of Alzheimer’s disease.
KeywordsAmyloid Precursor Protein Familial Hypercholesterolemia Induce Tyrosine Phosphorylation ApoE Receptor Density Lipoprotein Receptor Gene Family
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