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  • Review Article
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Reelin, lipoprotein receptors and synaptic plasticity

Nature Reviews Neuroscience volume 7, pages 850–859 (2006)Cite this article

Key Points

  • 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.

Abstract

Apolipoprotein E (APOE) is a cholesterol transport protein and an isoform-specific major risk factor for neurodegenerative diseases. The lipoprotein receptors that bind APOE have recently been recognized as pivotal components of the neuronal signalling machinery. The interaction between APOE receptors and one of their ligands, reelin, allows them to function directly as signal transduction receptors at the plasma membrane to control not only neuronal positioning during brain development, but also synaptic plasticity in the adult brain. Here, we review the molecular mechanisms through which APOE, cholesterol, reelin and APOE receptors control synaptic functions that are essential for cognition, learning, memory, behaviour and neuronal survival.

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Figure 1: Reelin-initiated signalling events in neurons.
Figure 2: Expression of reelin in the adult rodent brain.
Figure 3: Regulation of the NMDA receptor complex at the synapse.
Figure 4: Potential roles of APOE in neurons or in the synapse and possible implications for Alzheimer's disease.

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Acknowledgements

The authors acknowledge support by grants from the National Institutes of Health.

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Authors and Affiliations

  1. Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, 75390, Texus, USA

    Joachim Herz & Ying Chen

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  1. Joachim Herz
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Correspondence to Joachim Herz.

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FURTHER INFORMATION

Herz's laboratory

Glossary

Preplate

The preplate or primordial plexiform layer (PPL) is a layer composed of afferent and efferent fibres and scattered neurons above the ventricular zone at the embryonic stages of development (Carnegie stages 14–22).

Cortical plate

Outer neural tube region that post-mitotic neuroblasts migrate to along radial glia to form adult cortical layers.

Lissencephaly

Literally meaning 'smooth brain', lissencephaly is a human brain disorder that is characterized by the absence or reduction of the cerebral convolutions.

Quantitative trait loci

(QTLs). Genetic polymorphisms that affect the expression of a continuously distributed phenotype. Typically, QTLs are statistically associated with trait variations that depend on multiple interacting loci.

Long-term potentiation

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency stimulation of afferent pathways. It is measured both as the amplitude or differential of excitatory postsynaptic potentials and as the magnitude of the postsynaptic cell population spike. LTP is most frequently studied in the hippocampus and is often considered to be the cellular basis of learning and memory in vertebrates.

Morris water maze test

A task used to assess long-term spatial memory, most commonly in rodents. Animals use an array of extra-maze cues to locate a hidden escape platform that is submerged below the water surface. Learning in this task is hippocampus-dependent.

Ganglionic eminence

The proliferative zone of the ventral telencephalon, which gives rise to the basal ganglia, and also generates some cortical neurons and glia. It consists of lateral, caudal and medial subdivisions.

Late-phase LTP

Transcription- and translation-dependent LTP that is typically induced with multiple, spaced trains of high-frequency stimulation. This type of LTP persists for more than 3 hours.

Alternative splicing

A post-transcriptional process through which a pre-mRNA molecule, containing several introns and exons, can lead to different functional mRNA molecules, and consequently proteins, that originate from a single gene.

Dominant-negative

Describes a mutant molecule that could form a heteromeric complex with the normal molecule, knocking out the activity of the entire complex.

Long-term depression

(LTD). A long-lasting decrease in synaptic strength that can be induced in hippocampal area CA1 by either low-frequency stimulation (NMDA receptor-dependent) or stimulation of group I metabotropic glutamate receptors.

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Herz, J., Chen, Y. Reelin, lipoprotein receptors and synaptic plasticity. Nat Rev Neurosci 7, 850–859 (2006). https://doi.org/10.1038/nrn2009

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