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
, 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.
Chronic cerebral ischemia may accelerate clinicopathological changes in Alzheimer's disease. We have examined whether chronic cerebral hypoperfusion accelerates amyloid b deposition in amyloid ...protein precursor transgenic (APP-Tg) mouse. At 5, 8, and 11 months of age, C57Bl/6J male mice overexpressing a mutant form of the human APP bearing the both Swedish (K670N/M671L) and the Indiana (V717F) mutations (APPSwInd) and their litterrmates were subjected to either sham operation or bilateral carotid artery stenosis (BCAS) using microcoils with an internal diameter of 0.18 mm (short-period group). One month after the sham operation or BCAS, these animals were examined by immunohistochemistry for glial fibrillary acidic protein, amyloid b sub(1) sub(-) sub(4) sub(0) (Ab sub(1) sub(-) sub(4) sub(0)), amyloid b sub(1) sub(-) sub(4) sub(2) (Ab sub(1) sub(-) sub(4) sub(2)), as well as Western blotting and filter assay for Ab. Another batch of the littermates of APPSwInd mice were subjected to either sham operation or BCAS at 3 months and were examined in the same manner after survival for 9 months (long-period group). In the BCAS-treated group, the white matter was rarefied and astroglia was proliferated. Amyloid b sub(1) sub(-) sub(4) sub(0) immunoreactivity was found in a few axons in the white matter after BCAS, whereas Ab sub(1) sub(-) sub(4) sub(2) was accumulated in the scattered cortical neurons and the axons at ages of 6 months and thereafter in the short- and long-period groups. In the neuropil, both Ab sub(1) sub(-) sub(4) sub(0) and Ab sub(1) sub(-) sub(4) sub(2) were deposited in the sham-operated and BCAS-treated mice at ages of 9 and 12 months. There were no differences between the short-period group at ages of 12 months and the long-period group. Filter assay showed an increase of Ab fibrils in the extracellular enriched fraction. Taken together, chronic cerebral hypoperfusion increased Ab fibrils and induced Ab deposition in the intracellular compartment and, therefore, may accelerate the pathological changes of Alzheimer's disease.
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