Dementia Japan27:136-150, 2013

The molecular basis on the mechanism of synaptic degeneration and loss in Alzheimer's disease

Shun Shimohama

Department of Neurology, School of Medicine, Sapporo Medical University

    Synaptic loss, which strongly correlates with the decline of cognitive function, is one of the pathological hallmarks of Alzheimer's disease (AD).  N-cadherin is a cell adhesion molecule essential for synaptic contact and is involved in the intracellular signaling pathway at the synapses.  We found that N-cadherin is sequentially cleaved by ADAM10 and presenilin1(PS1)/γ-secretase and that GSK3β activity modifies the localization and function of PS1.  The association of N-cadherin-mediated synaptic contact by Aβ may underlie the pathological basis of synaptic degeneration and loss.  Synaptic integrity is morphologically maintained by the precise regulation of actin assembly.  We found abnormal accumulation of a key molecule for actin assembly in neurofibrillary tangles (NFTs) of AD brain and that the accumulation requires not only tau pathology but also Aβ-mediated GSK3β activity modification using transgenic mouse models of AD.  Further studies on the interaction between N-cadherin-mediated synaptic contact and actin assembly may contribute to find the molecular basis on the mechanism of synaptic degeneration and loss in AD.

Address correspondence to Dr. Shun Shimohama, Department of Neurology, School of Medicine, Sapporo Medical University (South-1 West-16, Chuo-ku, Sapporo 060-8543, Japan)