C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-β.
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.
Institute of Neuro- and Sensory Physiology, Medical Faculty, Heinrich-Heine-University Du¨ sseldorf, 40225 Du¨ sseldorf, Germany.
Aksana
A
Andreyeva
Katja
K
Nieweg
Katharina
K
Horstmann
Simon
S
Klapper
Andreas
A
Müller-Schiffmann
Carsten
C
Korth
Kurt
K
Gottmann
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D016229:Amyloid beta-Peptides / Q000494:pharmacology / Q000502:physiology*; D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015820:Cadherins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D002219:Carbamates / Q000494:pharmacology; D002478:Cells, Cultured; D004151:Dipeptides / Q000494:pharmacology; D005260:Female; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D055369:Miniature Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D053764:Presenilin-1 / Q000235:genetics / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D059748:Proteolysis; D013569:Synapses / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; D002219:Carbamates; D004151:Dipeptides; C410009:L 685458; D010446:Peptide Fragments; D053764:Presenilin-1; D053829:Amyloid Precursor Protein Secretases