Abstract
The biological fates of the key initiator of Alzheimer’s disease (AD), the amyloid precursor protein (APP), and a family of lipoprotein receptors, the low-density lipoprotein (LDL) receptor-related proteins (LRPs) and their molecular roles in the neurodegenerative disease process are inseparably interwoven. Not only does APP bind tightly to the extracellular domains (ECDs) of several members of the LRP group, their intracellular portions are also connected through scaffolds like the one established by FE65 proteins and through interactions with adaptor proteins such as X11/Mint and Dab1. Moreover, the ECDs of APP and LRPs share common ligands, most notably Reelin, a regulator of neuronal migration during embryonic development and modulator of synaptic transmission in the adult brain, and Agrin, another signaling protein which is essential for the formation and maintenance of the neuromuscular junction (NMJ) and which likely also has critical, though at this time less well defined, roles for the regulation of central synapses. Furthermore, the major independent risk factors for AD, Apolipoprotein (Apo) E and ApoJ/Clusterin, are lipoprotein ligands for LRPs. Receptors and ligands mutually influence their intracellular trafficking and thereby the functions and abilities of neurons and the blood-brain-barrier to turn over and remove the pathological product of APP, the amyloid-β peptide. This article will review and summarize the molecular mechanisms that are shared by APP and LRPs and discuss their relative contributions to AD.
Highlights
The biological fates of the key initiator of Alzheimer’s disease (AD), the amyloid precursor protein (APP), and a family of lipoprotein receptors, the low-density lipoprotein (LDL) receptor-related proteins (LRPs) and their molecular roles in the neurodegenerative disease process are inseparably interwoven
Lipoprotein receptors are involved in various mechanisms of APP-processing and amyloid β (Aβ)-clearance in several cell types including neurons, astrocytes, endothelial cells of the blood brain barrier (BBB), and ependymal cells of the blood cerebrospinal fluid (CSF) barrier (BCSFB; reviewed by Hoe and Rebeck, 2008; Marzolo and Bu, 2009; Wagner and Pietrzik, 2012; Lane-Donovan et al, 2014)
Lrad3 and Lrp10 have been shown to interact with APP, we briefly review them
Summary
Reviewed by: Eckart Förster, Ruhr University Bochum, Germany Claus Pietrzik, University of Mainz, Germany. The biological fates of the key initiator of Alzheimer’s disease (AD), the amyloid precursor protein (APP), and a family of lipoprotein receptors, the low-density lipoprotein (LDL) receptor-related proteins (LRPs) and their molecular roles in the neurodegenerative disease process are inseparably interwoven. Does APP bind tightly to the extracellular domains (ECDs) of several members of the LRP group, their intracellular portions are connected through scaffolds like the one established by FE65 proteins and through interactions with adaptor proteins such as X11/Mint and Dab. The ECDs of APP and LRPs share common ligands, most notably Reelin, a regulator of neuronal migration during embryonic development and modulator of synaptic transmission in the adult brain, and Agrin, another signaling protein which is essential for the formation and maintenance of the neuromuscular junction (NMJ) and which likely has critical, though at this time less well defined, roles for the regulation of central synapses.
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