Abstract
Apolipoprotein E (ApoE) genotype is the strongest predictor of Alzheimer’s Disease (AD) risk. ApoE is a cholesterol transport protein that binds to members of the Low-Density Lipoprotein (LDL) Receptor family, which includes LDL Receptor Related Protein 4 (Lrp4). Lrp4, together with one of its ligands Agrin and its co-receptors Muscle Specific Kinase (MuSK) and Amyloid Precursor Protein (APP), regulates neuromuscular junction (NMJ) formation. All four proteins are also expressed in the adult brain, and APP, MuSK, and Agrin are required for normal synapse function in the CNS. Here, we show that Lrp4 is also required for normal hippocampal plasticity. In contrast to the closely related Lrp8/Apoer2, the intracellular domain of Lrp4 does not appear to be necessary for normal expression and maintenance of long-term potentiation at central synapses or for the formation and maintenance of peripheral NMJs. However, it does play a role in limb development.
Highlights
Apolipoprotein E (ApoE) receptors are essential regulators of excitatory innervation of central and neuromuscular synapses
To study the functional importance of these motifs in vivo, we generated an allelic series of LDL Receptor Related Protein 4 (Lrp4) knock-in lines (KIs) [22]
These mice include: (1) Lrp4ECD/ECD, in which the intracellular domain (ICD) and transmembrane domain are deleted, resulting in a secreted extracellular domain (ECD) [10,19] (2) Lrp4WT-KI/WT-KI, in which a cDNA encoding the wild type ICD was knocked-in as a control; (3) Lrp4AS/AS, containing an alternatively spliced (AS) form of Lrp4 that truncates the ICD after the NPxY motif; (4) Lrp4AAAA/AAAA, in which the NPxY motif is mutated to AAAA; (5) Lrp4ΔPDZ/ΔPDZ, lacking the C-terminal PDZ-interaction motif; (6) Lrp4LDLR-ICD/LDLR-ICD, in which the Lrp4-ICD is replaced with the LDLR-ICD; and (7) Lrp4ΔICD/ΔICD, in which the ICD is replaced by a Myc-tag [10] and models an Lrp4 truncation found in cattle suffering from mulefoot disease [23] (Fig. 1A)
Summary
ApoE receptors are essential regulators of excitatory innervation of central and neuromuscular synapses. Lrp4 in Limb/Brain Development and Synaptic Plasticity
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