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

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.

Δ8-THC Protects against Amyloid Beta Toxicity Modulating ER Stress In Vitro: A Transcriptomic Analysis

“…We also found the downregulation of EDEM1 . It can modulate APP metabolism, and its overexpression is associated with a decrease in Aβ secretion [ 55 ]. Interestingly, EDEM1 can be upregulated by Δ 8 -THC pre-treatment.…”

Amyloid Precursor Protein and Alzheimer’s Disease

“…In cell cultures expressing APP, EDEM1 promotes APP targeting from the ER to the cytoplasm, where ERAD takes place. It stimulates the proteosome degradation of APP inside the cell and leads to a consequent decrease in Aβ40-42 production [144]. Golgi fragmentation was reported in AD pathology cases; however, the primary reason and consequence in the APP-Golgi relationship is still poorly understood.…”