Alzheimer's disease (AD) is characterized by the extracellular deposition of amyloid- (A), neurofibrillary tangle formation, and a microglial-driven inflammatory response. Chronic inflammatory activation compromises microglial clearance functions. Because peroxisome proliferator-activated receptor ␥ (PPAR␥) agonists suppress inflammatory gene expression, we tested whether activation of PPAR␥ would also result in improved microglial A phagocytosis. The PPAR␥ agonist pioglitazone and a novel selective PPAR␣/␥ modulator, DSP-8658, currently in clinical development for the treatment of type 2 diabetes, enhanced the microglial uptake of A in a PPAR␥-dependent manner. This PPAR␥-stimulated increase of A phagocytosis was mediated by the upregulation of scavenger receptor CD36 expression. In addition, combined treatment with agonists for the heterodimeric binding partners of PPAR␥, the retinoid X receptors (RXRs), showed additive enhancement of the A uptake that was mediated by RXR␣ activation. Evaluation of DSP-8658 in the amyloid precursor protein/presenilin 1 mouse model confirmed an increased microglial A phagocytosis in vivo, which subsequently resulted in a reduction of cortical and hippocampal A levels. Furthermore, DSP-8658-treated mice showed improved spatial memory performance. Therefore, stimulation of microglial clearance by simultaneous activation of the PPAR␥/RXR␣ heterodimer may prove beneficial in prevention of AD.
All three mammalian EDEM family members possess mannosidase activity and are necessary for glycoprotein degradation, but EDEM2 performs a unique, rate-limiting, first mannose trimming step upstream of EDEM1 and EDEM3.
The endoplasmic reticulum (ER) membrane-bound transcription factors ATF6α and ATF6β mediate adjustment of chaperone levels to increased demands in the ER, which is essential for development of the notochord; the latter synthesizes and secretes large amounts of extracellular matrix proteins to serve as the body axis before formation of the vertebra.
Sequential mannose trimming of N-glycan (Man9GlcNAc2 -> Man8GlcNAc2 -> Man7GlcNAc2) facilitates endoplasmic reticulum-associated degradation of misfolded glycoproteins (gpERAD). Our gene knockout experiments in human HCT116 cells have revealed that EDEM2 is required for the first step. However, it was previously shown that purified EDEM2 exhibited no α1,2-mannosidase activity toward Man9GlcNAc2 in vitro. Here, we found that EDEM2 was stably disulfide-bonded to TXNDC11, an endoplasmic reticulum protein containing five thioredoxin (Trx)-like domains. C558 present outside of the mannosidase homology domain of EDEM2 was linked to C692 in Trx5, which solely contains the CXXC motif in TXNDC11. This covalent bonding was essential for mannose trimming and subsequent gpERAD in HCT116 cells. Furthermore, EDEM2-TXNDC11 complex purified from transfected HCT116 cells converted Man9GlcNAc2 to Man8GlcNAc2(isomerB) in vitro. Our results establish the role of EDEM2 as an initiator of gpERAD, and represent the first clear demonstration of in vitro mannosidase activity of EDEM family proteins.
The unfolded protein response (UPR) handles misfolded proteins that accumulate in the ER, but it is unclear when or why vertebrates utilize different UPR transducers. Ishikawa et al. find that UPR transducer use changes during development of the notochord in medaka fish according to the length of collagen synthesized, from ATF6 alone (for folding of short-chain collagen) to ATF6 plus BBF2H7 (for folding and export of long-chain collagen).
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