Synapse destabilization is thought to be a major early pathophysiological event in the aetiology of Alzheimer's disease (AD). The proteolytic generation of b-amyloid (Ab) peptides from amyloid precursor protein (APP) is well described. However, the molecular mechanisms of the deleterious synaptic actions of Ab are incompletely understood. Transsynaptically interacting cell adhesion molecules have been proposed to play a crucial role in the long-term maintenance system of individual synapses, which might counteract synapse destabilization. N-cadherin is a prototypic synaptic adhesion molecule, which is - similar to APP- also proteolyticaly processed by a- and g-secretase. Dysfunction of these proteolytic processing mechanisms leads to the accumulation of a C-terminal fragment of N-cadherin (NcadCTF1), which inhibits transsynaptic N-cadherin adhesion and thus might enhance Ab induced synapse destabilization.

To experimentally study the role of transsynaptic N-cadherin adhesion in Ab induced synapse impairment, we investigated the effects of Ab peptides on spontaneous AMPA receptor-mediated miniature EPSCs (AMPA mEPSCs) in cultured cortical neurons. Incubation with Ab peptides for three days resulted in a reduced frequency and amplitude of AMPA mEPSCs, whereas no significant effects were seen after two days of incubation. Inhibition of the N-cadherin adhesion system by function blocking peptides (INP peptides) led to an acceleration of the Ab effect on the frequency of AMPA mEPSCs, which occurred already after two days of incubation. Increasing the presence of NcadCTF1 by either overexpression of human NcadCTF1 or by inhibiting the function of g-secretase led to a similar acceleration of Ab effects on AMPA mEPSCs. Semi-quantitative Western analysis of the expression of NcadCTF1 in the post-mortem brains of late-onset AD patients revealed a clearly enhanced presence in about half of the samples. This indicates that the accelerating effect of NcadCTF1 on Ab induced synapse impairment might be of relevance in the progression of AD. In particular, this might play an important role in familial AD, where hypofunctional presenilin mutations have been described.