Functional Roles of the Interaction of APP and Lipoprotein Receptors

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.

The metalloprotease ADAMTS4 generates N-truncated Aβ4–x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer’s disease

“…Yet another possibility is that ADAMTS4 is secreted by oligodendrocytes and taken up by neurons through endocytosis, leading to the processing of APP by ADAMTS4 in intracellular vesicular compartments. Indeed, in cartilage, it has been demonstrated that extracellular ADAMTS4 can be internalized via low density lipoprotein receptor-related protein (LRP1), which is abundantly expressed in neurons [57,81]. Further studies are required to clarify this issue, but all three of these possibilities conform to our immunohistochemical detection of Aβ4-x peptides in white matter structures and their co-localization with APP in fiber tracts of 5xFAD mice (see below).…”

Phosphorylation of FE65 at threonine 579 by GSK3β stimulates amyloid precursor protein processing

“…In addition to APP, FE65 interacts with LRP1 via its PTB1 domain. It is proposed that LRP1/FE65/APP promotes amyloidogenic processing of APP by increasing endocytosis that makes APP more accessible to the endosomal BACE1 and γ-secretase 26 . The availability of FE65 for recruiting LRP1 and APP may be crucial for the formation of the trimeric complex.…”

WNT Signaling and Bone: Lessons From Skeletal Dysplasias and Disorders

“…Most LRP receptors have in the intracellular region at least one NPxY-(endocytosis) motif. However, LRP5/6 are lacking this motif (105). Mutations in three members of the LRP family, namely, LRP4, LRP5, and LRP6, are reported to result in rare skeletal disorders (51,106,107).…”