Insulin-regulated β-amyloid protein trafficking: Stimulated secretion and reduced intracellular accumulation of Aβ in neuronal cell cultures

Abstract

Dysfunction in the synapse is recognized as an early and the primary pathological process in Alzheimer’s disease (AD). N-cadherin, an essential adhesion molecule for excitatory synaptic contact, forms a complex with presenilin 1 (PS1) and β-catenin in the synaptic membrane. N-cadherin is sequentially cleaved by ADAM10 and PS1/γ-secretase, producing a cytoplasmic fragment, N-cadherin C-terminal fragment (Ncad/CTF2) after NMDA receptor stimulation [Marambaud P, Wen PH, Dutt A, Shioi J, Takashima A, Siman R, Robakis NK (2003) A CBP binding transcriptional repressor produced by the PS1/epsilon-cleavage of N-cadherin is inhibited by PS1 FAD mutations. Cell 114:635–645; Reiss K, Maretzky T, Ludwig A, Tousseyn T, de Strooper B, Hartmann D, Saftig P (2005) ADAM10 cleavage of N-cadherin and regulation of cell-cell adhesion and beta-catenin nuclear signalling. EMBO J 24:1762]. Ncad/CTF2 translocates to the nucleus together with β-catenin to enhance β-catenin nuclear signaling [Uemura K, Kihara T, Kuzuya A, Okawa K, Nishimoto T, Bito H, Ninomiya H, Sugimoto H, Kinoshita A, Shimohama S (2006a) Activity-dependent regulation of beta-catenin via epsilon-cleavage of N-cadherin. Biochem Biophys Res Commun 345:951–958]. To examine whether an impairment of N-cadherin metabolism is involved in AD pathogenesis, we investigated the effect of amyloid β peptide (Aβ) treatment on sequential N-cadherin cleavage. Here, we demonstrate that both synthetic and cell-derived Aβ species inhibit ectodomain shedding of mouse N-cadherin. Inhibition of N-cadherin cleavage by Aβ treatment was suggested to be mediated by the enhanced endocytosis of NMDA receptor, resulting in reduced turnover of N-cadherin. Since both N-cadherin and β-catenin are essential for synaptic plasticity, impairment of N-cadherin cleavage caused by Aβ may underlie the synapse toxicity involved in AD pathogenesis.