Effects of liraglutide on neurodegeneration, blood flow and cognition in Alzheimer´s disease - protocol for a controlled, randomized double-blinded trial.

INTRODUCTION: Type 2 diabetes (DM-2) increases the risk of developing Alzheimer´s disease (AD), and patients with AD are more likely to develop DM-2. DM-2 and AD share some pathophysiological features. In AD, amyloid-ß (Aß) is accumulated as extracellular plaques in the gray matter of the brain, while in DM-2 islet amyloid polypeptide (IAPP) is accumulated in the pancreas. Premature cellular degeneration is seen in both diseases. Glucagon-like peptide-1 (GLP-1) reduces the amount of Aß and improves cognition in animal studies. The present study tests the hypothesis that treatment with the long-acting GLP-1 receptor agonist liraglutide affects the accumulation of Aß in patients with AD. MATERIAL AND METHODS: This is a randomized, controlled, double-blinded intervention study with AD patients treated for six months with liraglutide (n = 20) or placebo (n = 20). The primary outcome is change in deposition of Aß in the central nervous system (CNS) by Pittsburgh compound B positron emission tomography (PET). The secondary outcome is evaluation of cognition using a neuro-psychological test battery, and examination of changes in glucose uptake in the CNS by 18F-fluoro-deoxy-glucose PET. Finally, a perfusion-weighted magnetic resonance imaging with contrast will be performed to evaluate blood flow. CONCLUSION: No registered drug affects the deposition of Aß in the brain of AD patients. Our goal is to find a new therapeutic agent that alters the pathophysiology in AD patients by decreasing the formation of Aß plaques and thereby presumably improves the cognitive function. FUNDING: The trial is investigator-initiated and investigator-driven and is supported by Novo Nordisk Scandinavia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01469351.

The metalloprotease disintegrin ADAM8. Processing by autocatalysis is required for proteolytic activity and cell adhesion.

ADAMs (a disintegrin and metalloprotease domains) are metalloprotease and disintegrin domain-containing transmembrane glycoproteins with proteolytic, cell adhesion, cell fusion, and cell signaling properties. ADAM8 was originally cloned from monocytic cells, and its distinct expression pattern indicates possible roles in both immunology and neuropathology. Here we describe our analysis of its biochemical properties. In transfected COS-7 cells, ADAM8 is localized to the plasma membrane and processed into two forms derived either by prodomain removal or as remnant protein comprising the extracellular region with the disintegrin domain at the N terminus. Proteolytic removal of the ADAM8 propeptide was completely blocked in mutant ADAM8 with a Glu(330) to Gln exchange (EQ-A8) in the Zn(2+) binding motif (HE(330)LGHNLGMSHD), arguing for autocatalytic prodomain removal. In co-transfection experiments, the ectodomain but not the entire MP domain of ADAM8 was able to remove the prodomain from EQ-ADAM8. With cells expressing ADAM8, cell adhesion to a substrate-bound recombinant ADAM8 disintegrin/Cys-rich domain was observed in the absence of serum, blocked by an antibody directed against the ADAM8 disintegrin domain. Soluble ADAM8 protease, consisting of either the metalloprotease domain or the complete ectodomain, cleaved myelin basic protein and a fluorogenic peptide substrate, and was inhibited by batimastat (BB-94, IC(50) approximately 50 nm) but not by recombinant tissue inhibitor of matrix metalloproteinases 1, 2, 3, and 4. Our findings demonstrate that ADAM8 processing by autocatalysis leads to a potential sheddase and to a form of ADAM8 with a function in cell adhesion.