Abstract
The low-density lipoprotein receptor-related protein 1, LRP1, interacts with APP and affects its processing. This is assumed to be mostly caused by the impact of LRP1 on APP endocytosis. More recently, also an interaction of APP and LRP1 early in the secretory pathway was reported whereat retention of LRP1 in the ER leads to decreased APP cell surface levels and in turn, to reduced Aβ secretion. Here, we extended the biochemical and immunocytochemical analyses by showing via live cell imaging analyses in primary neurons that LRP1 and APP are transported only partly in common (one third) but to a higher degree in distinct fast axonal transport vesicles. Interestingly, co-expression of LRP1 and APP caused a change of APP transport velocities, indicating that LRP1 recruits APP to a specific type of fast axonal transport vesicles. In contrast lowered levels of LRP1 facilitated APP transport. We further show that monomeric and dimeric APP exhibit similar transport characteristics and that both are affected by LRP1 in a similar way, by slowing down APP anterograde transport and increasing its endocytosis rate. In line with this, a knockout of LRP1 in CHO cells and in primary neurons caused an increase of monomeric and dimeric APP surface localization and in turn accelerated shedding by meprin β and ADAM10. Notably, a choroid plexus specific LRP1 knockout caused a much higher secretion of sAPP dimers into the cerebrospinal fluid compared to sAPP monomers. Together, our data show that LRP1 functions as a sorting receptor for APP, regulating its cell surface localization and thereby its processing by ADAM10 and meprin β, with the latter exhibiting a preference for APP in its dimeric state.
Highlights
The amyloid precursor protein (APP) is a type I transmembrane protein that has first been identified related in association with Alzheimer’s disease (AD) as representing the precursor of amyloid β (Aβ) peptides (Kang et al, 1987)
In vivo analyses were performed with tamoxifen-inducible 5xFAD mice lacking Lrp1 in brain endothelial and choroid plexus epithelial cells (5xFAD/Lrp1BE−/−). 5xFAD mice, which represent a well-established AD model harboring 3 APP mutations and 2 PSEN1 mutations that are linked to FAD, served as LRP1 expressing controls
As we found that neurons secrete disulfide-bound dimerized sAPP, we wondered if monomeric and dimeric APP are transported along the secretory pathway in the same or diverse types of transport vesicles
Summary
The amyloid precursor protein (APP) is a type I transmembrane protein that has first been identified related in association with Alzheimer’s disease (AD) as representing the precursor of amyloid β (Aβ) peptides (Kang et al, 1987). Those peptides generated by sequential cleavage of APP by β- and γ-secretases were shown to be a major component of senile plaques found in the brains of AD patients (Merz et al, 1983; Masters et al, 1985). Whether sAPP dimers are generated in vivo in neurons, which secretases are required and what might be the role of LRP1 in this context, is unknown yet
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