C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-β

Abstract

The aetiology of Alzheimer's disease is thought to include functional impairment of synapses and synapse loss as crucial pathological events leading to cognitive dysfunction and memory loss. Oligomeric amyloid-β peptides are well known to induce functional damage, destabilization and loss of brain synapses. However, the complex molecular mechanisms of amyloid-β action resulting ultimately in synapse elimination are incompletely understood, thus limiting knowledge of potential therapeutic targets. Under physiological conditions, long-term synapse stability is mediated by trans-synaptically interacting adhesion molecules such as the homophilically binding N-cadherin/catenin complexes. In this study, we addressed whether inhibition of N-cadherin function affects amyloid-β-induced synapse impairment. We found that blocking N-cadherin function, both by specific peptides interfering with homophilic binding and by expression of a dominant-negative, ectodomain-deleted N-cadherin mutant, resulted in a strong acceleration of the effect of amyloid-β on synapse function in cultured cortical neurons. The frequency of AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor-mediated miniature excitatory postsynaptic currents was reduced upon amyloid-β application much earlier than observed in controls. We further hypothesized that ectodomain-shed, transmembrane C-terminal fragments that are generated during N-cadherin proteolytic processing might similarly enhance amyloid-β-induced synapse damage. Indeed, expression of human N-cadherin C-terminal fragment 1 strongly accelerated amyloid-β-triggered synapse impairment. Ectodomain-shed N-cadherin C-terminal fragment 1 is further proteolytically cleaved by γ-secretase. Therefore, both pharmacological inhibition of γ-secretase and expression of the dominant-negative presenilin 1 mutant L166P were used to increase the presence of endogeneous N-cadherin C-terminal fragment 1. Under these conditions, we again found a strong acceleration of amyloid-β-induced synapse impairment, which could be compensated by over-expression of full-length N-cadherin. Intriguingly, western blot analysis of post-mortem brains from patients with Alzheimer's disease revealed an enhanced presence of N-cadherin C-terminal fragment 1. Thus, an inhibition of N-cadherin function by proteolytically generated N-cadherin C-terminal fragment 1 might play an important role in Alzheimer's disease progression by accelerating amyloid-β-triggered synapse damage.

Cadherins and catenins in dendrite and synapse morphogenesis

“…93 Interestingly, the blockade of Ncadherin function accelerated Ab synaptotoxicity, and furthermore patients with Alzheimer's disease have increased level of proteolytically-cleaved N-cadherin C-terminal fragment 1 94 . However, no evidence for its genetic association with the disease has yet been reported.…”

Flotillins in intercellular adhesion – from cellular physiology to human diseases

“…In this neurodegenerative disease, Ncadherin and flotillins contribute to the production of amyloid-b peptide, the major component of senile plaques (Andreyeva et al, 2012) (Bitsikas et al, 2014). Both N-cadherin and flotillins facilitate dimerization of the amyloid-b peptide precursor APP and its subsequent endocytosis, thereby allowing its cleavage in the acidic endosomal compartment, which increases generation of the amyloidb peptide (Asada-Utsugi et al, 2011;Schneider et al, 2008).…”

Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

“…For example, inhibition of N-cadherin function has been reported to accelerate Ab-triggered synapse damage. 60 Moreover, dissociation of N-cadherin-mediated synaptic contact by Ab has been proposed to cause neuronal cell death, synaptic loss and tau phosphorylation in AD brain. 61 Two affected siblings in family ND6 show the presence of FAD-CNV6, a 0.73-Mb intergenic gain in CN.…”