LRP1 Modulates APP Intraneuronal Transport and Processing in Its Monomeric and Dimeric State

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.

Reciprocal Modulation Between Amyloid Precursor Protein and Synaptic Membrane Cholesterol Revealed By Live Cell Imaging

“…Because the cytoplasmic domain is intact in the CTFs, APP/CTF heterodimers can be as resistant to LRP1 binding as APP homodimers. Long term inhibition of LRP1 binding to APP in cell lines (Ulery et al, 2000) and knocking out LRP1 in primary neurons (Herr et al, 2017) both resulted in drastic increases in APP surface fraction and production of sAPP. If S inhibition increases the surface fraction of APP through promotion of heterodimerization of APP and CTF, it logically follows that αS or βS inhibition would decrease the surface fraction by increasing full length APP and decreasing the production of CTFs, which is in fact what we observe (Figure 4).…”

“…If so, the explanation for our data can involve more than synaptic vesicle endocytosis as CME is essential for many other forms of surface membrane internalization. For example, the well-established LRP1-mediated endocytosis of APP is via CME as well (Herr et al, 2017). Reduced clustering in lipid rafts is also a potential contributor to reduced endocytosis (Schneider et al, 2008).…”

Pur-alpha participates in the progression of Alzheimer's disease through direct and indirect ways

“…LRP1 is a member of the low-density lipoprotein receptor family [35], which has four extracellular ligand binding domains that bind to different ligands, including APP [36], apolipoprotein E. (Apolipoprotein E) [37], and α2 macroglobulin (α2M) [35]. LRP1 can be combined with APP before it is cut by furin [38], which slows APP movement [39], and promotes further processing of the protein [40]. LRP1 binds to APP to facilitate processing of APP, but this effect appears to increase the production of Ab [41].…”

Pur-alpha participates in the progression of Alzheimer's disease through direct and indirect ways

“…(Apolipoprotein E) [37], and α2 macroglobulin (α2M) [35]. LRP1 can be combined with APP before it is cut by furin [38], which slows APP movement [39], and promotes further processing of the protein [40]. LRP1 binds to APP to facilitate processing of APP, but this effect appears to increase the production of Aβ [41].…”