EDEM1 Regulates Amyloid Precursor Protein (APP) Metabolism and Amyloid-β Production

Jowita Nowakowska-Gołacka,Hanna Sominka,Monika Słomińska-Wojewódzka,Natalia Sowa-Rogozińska,Justyna Czapiewska

doi:10.3390/ijms23010117

Jowita Nowakowska-Gołacka, Hanna Sominka + Show 3 more

Open Access

https://doi.org/10.3390/ijms23010117

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Abstract

Endoplasmic reticulum (ER) degradation-enhancing α-mannosidase-like protein 1 (EDEM1) is a quality control factor directly involved in the endoplasmic reticulum-associated degradation (ERAD) process. It recognizes terminally misfolded proteins and directs them to retrotranslocation which is followed by proteasomal degradation in the cytosol. The amyloid-β precursor protein (APP) is synthesized and N-glycosylated in the ER and transported to the Golgi for maturation before being delivered to the cell surface. The amyloidogenic cleavage pathway of APP leads to production of amyloid-β (Aβ), deposited in the brains of Alzheimer’s disease (AD) patients. Here, using biochemical methods applied to human embryonic kidney, HEK293, and SH-SY5Y neuroblastoma cells, we show that EDEM1 is an important regulatory factor involved in APP metabolism. We find that APP cellular levels are significantly reduced after EDEM1 overproduction and are increased in cells with downregulated EDEM1. We also report on EDEM1-dependent transport of APP from the ER to the cytosol that leads to proteasomal degradation of APP. EDEM1 directly interacts with APP. Furthermore, overproduction of EDEM1 results in decreased Aβ40 and Aβ42 secretion. These findings indicate that EDEM1 is a novel regulator of APP metabolism through ERAD.

Highlights

Alzheimer’s disease (AD) is irreversible, progressive, and the most common brain disorder that results in dementia, mainly in the elderly
Aβ is formed by sequential proteolytic cleavage of a large, type 1 transmembrane glycoprotein, the amyloid-β precursor protein (APP), that is ubiquitously expressed in the neuronal and non-neuronal cells
Some evidence shows that APP695 is preferentially involved in Aβ production [12], whereas other evidence demonstrates that APP751 and APP770 overexpression in the brain is primarily associated with the Aβ release [13]

Summary

Introduction

Alzheimer’s disease (AD) is irreversible, progressive, and the most common brain disorder that results in dementia, mainly in the elderly. APP is incorporated into the endoplasmic reticulum (ER) membrane, entering the constitutive secretory pathway Along this pathway, APP maturates by being subjected to extensive post-translational modifications that affect its sorting and trafficking (for a review see reference [10]). Different forms of APP are much more diverse, as there are about ten variants of this protein arising from alternative splicing of exons 7 and 8 The length of these isoforms varies from 639 to 770 amino acids. Some evidence shows that APP695 is preferentially involved in Aβ production [12], whereas other evidence demonstrates that APP751 and APP770 overexpression in the brain is primarily associated with the Aβ release [13] It is not clear whether APP isoforms trigger the amyloidogenic pathway in the same way. Cleavage by secretases results in formation of 39–43 residue peptides, among which Aβ40 , as well as Aβ42 , become components of the senile plaques

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