Mice with cleavage-resistant N-cadherin exhibit synapse anomaly in the hippocampus and outperformance in spatial learning tasks.

N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2 R714G, I715D, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 s than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.

Successful allogeneic blood stem cell transplantation for aplastic anemia in a patient with renal insufficiency requiring dialysis.

A 27-year-old man with aplastic anemia and renal insufficiency requiring dialysis underwent allogeneic PBSCT. The preparative regimen consisted of melphalan, ATG and TLI. GVHD prophylaxis consisted of cyclosporine and prednisolone. He was dialyzed prior to administration of melphalan and at 24 and 72 h after it. Otherwise, the dialysis schedule was unchanged, at three times a week. Engraftment was rapid. Regimen-related toxicity was minimal. Pharmacokinetic parameters of melphalan were not significantly altered with its plasma half-life 1.5 h. Patients with renal failure can receive allogeneic HSCT, and a combination of melphalan, ATG and TLI may serve as an alternative to CY and ATG.