Reelin, lipoprotein receptors and synaptic plasticity

The low-density lipoprotein (LDL) receptor gene family forms a class of multifunctional lipoprotein receptors that mediate the cellular uptake of cholesterol and other lipids. They also transmit, modulate and integrate a broad range of extracellular signals that include, for example, the control of cellular proliferation, migration, development and neurotransmission.Reelin, a large extracellular signalling molecule, controls neuronal migration and positioning during brain development by binding to the apolipoprotein E (APOE) receptors very low-density lipoprotein receptor (VLDLR) and APOE receptor 2 (APOER2).In the adult brain, reelin signalling assumes a new role in the control of synaptic plasticity by regulating the activity of NMDA (N-methyl-D-aspartate) receptors. This also involves differential splicing of one of the reelin receptors, APOER2.Reelin signalling through APOE receptors also stabilizes microtubules and prevents tau (τ) hyperphosphorylation and thereby possibly the formation of neurofibrillary tangles, a histopathological hallmark of Alzheimer's disease.Genetic defects in the reelin pathway disrupt normal brain development and cause mental retardation in humans.Cholesterol is a key component of cellular membranes and as such has a crucial role in synaptic functions, as well as in the processing of the amyloid-β (Aβ) protein. This short peptide is not only the main component of the plaques in the brains of patients with Alzheimer's disease but also a modulator of synaptic plasticity.APOE, a cholesterol-carrying ligand for the lipoprotein receptors of the LDL receptor gene family, is genetically associated with late-onset Alzheimer's disease. The emerging functions of Aβ, cholesterol and APOE receptors in neurons and particularly in synapses point towards a probable role for these signal-transducing lipoprotein receptors in the disease process.