Alzheimer's disease (AD) is the most prevalent cause of dementia. In AD, synaptic loss is one of the principal pathological hallmarks, and correlates with the severity of cognitive impairment. N-cadherin is a representative cell adhesion molecule, which plays an important role in synapse formation, especially in hippocampal excitatory neurons. N-cadherin not only maintains synaptic structure, but also actively regulates synaptic plasticity. N-cadherin undergoes sequential cleavage by ADAM10 and PS1, however, the significance of the cleavage has not been clarified. To investigate for the significance of N-cadherin cleavage in vivo, we analyzed ADAM10-mediated cleavage-defective (i.e. ectodomain shedding deficient) N-cadherin knock-in (KI) mice.
As expected, the cleavage of N-cadherin by ADAM10 was not observed in the brain or primary neuron obtained from the KI mice.
KI mice were viable and retained normal reproduction capacity, but demonstrated weight loss. Electronmicroscopic analysis of hippocampal CA3 region showed significant decrease of PSD area in KI mice as compared to WT mice but showed no difference in spine volume.
Interestingly, physical dissector method showed increased synaptic density in KI mice. Accordingly, KI mice showed significantly better performance in the radial maze test compared to WT mice.
Thus, our results suggested that the inhibition of N-cadherin cleavage by ADAM10 might lead to stabilization of synapses, leading to better working memory.