A fresh look at an ancient receptor family: Emerging roles for low density lipoprotein receptors in synaptic plasticity and memory formation

Abstract

The well-known family of low-density lipoprotein receptors represents a collection of ancient membrane receptors that have been remarkably conserved throughout evolution. These multifunctional receptors, known to regulate cholesterol transport, are becoming increasingly interesting to the neuroscience community due to their ability to transduce a diversity of extracellular signals across the membrane in the adult CNS. Their roles in modulating synaptic plasticity and necessity in hippocampus-specific learning and memory have recently come to light. In addition, genetic, biochemical and behavioral studies have implicated these signaling systems in a number of human neurodegenerative and neuropsychiatric disorders involving loss of cognitive ability, such as Alzheimer’s disease, schizophrenia and autism. This review describes the known functions of these receptors and discusses their potential role in processes of synaptic regulation and memory formation.

Introduction

A decade ago it was widely held that the human genome likely consisted of more than 100,000 functioning genes. When sequencing was finished in 2004, the International Human Genome Sequencing Consortium (HGSC) estimated the number would be closer to the order of 20,000 genes, only one-third greater than that of the simple nematode C. elegans. Other than the speculated mechanisms of RNA processing or the multi-subunit composition of certain proteins, one explanation for the lower number of expected functional genes is the evolution of certain proteins to serve in multiple capacities. This phenomenon is particularly prominent in the mammalian CNS where molecules that have important regulatory roles outside the CNS, such as kinases (MAPK, PKA, PKC), receptors (nicotinic acetylcholine, estrogen receptors) and transcription factors (C/EBP, CREB, ELK-1) and translation proteins (4EBP, CPEB, EIF4), have been co-opted in neuronal function in general and processes vital to human cognition in particular. Thus, it is not surprising that key components of the cellular machinery underlying complex neuronal networks are composed of highly conserved genes representing the evolutionarily “oldest” proteins capable of carrying out multiple cellular functions. This idea is supported by seminal research in Aplysia, Hermissenda, C. elegans and Drosophila demonstrating that molecular mechanisms subserving memory formation are strongly conserved over the course of evolution (Bailey et al., 2004, Crow, 2004, Meller and Davis, 1996, Rankin, 2004). The evolutionarily ancient low density lipoprotein receptors (LDLRs) represent one such multifunctional cell surface protein family that has been recently discovered to play roles in extracellular protein endocytosis, cross-membrane signal transduction and modulation of synaptic function.

Historically, the most intensive studies involving the LDL family of receptors have focused on their importance in hepatic cholesterol transport and metabolism. Genetic analysis linking early onset Alzheimer’s disease (AD) with polymorphisms in specific LDL receptor and two ligands of LDLRs, apolipoprotein E (apoE) and α-2-macroglobulin, confirms that these receptors had functions beyond simple cholesterol homeostasis. However, the discoveries that LDL receptors are involved in modulation of hippocampal synaptic plasticity and necessary for normal learning and memory have forced neurobiologists to recognize the importance of LDLRs in CNS function. The ability to endocytose cellular nutrients, clear extracellular matrix proteins, transduce signals from multiple ligands and activate numerous signal transduction pathways truly places this family of receptors in a very exclusive class of multifunctional receptor proteins. Thus, the LDL receptor family represents an excellent example of adapting conserved cell surface receptors to divergent functions in many cell types.