C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-β
C-terminal fragment of N-cadherin accelerates synapse destabilization by amyloid-β
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DOI：
10.1093/brain/aws120
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发表时间：
2012-07-01
期刊：
影响因子：
14.5
通讯作者：
Gottmann, Kurt
中科院分区：
文献类型：
--
作者：
Andreyeva, Aksana;Nieweg, Katja;Gottmann, Kurt
阿尔茨海默病的病因学被认为包括突触功能障碍和突触丢失，这些是导致认知功能障碍和记忆丧失的关键病理事件。众所周知，寡聚体淀粉样β多肽可导致脑部突触的功能损伤、不稳定和丢失。然而，淀粉样β蛋白作用最终导致突触消除的复杂分子机制尚不完全清楚，因此限制了对潜在治疗靶点的了解。在生理条件下，突触的长期稳定性是由跨突触相互作用的黏附分子介导的，例如同型结合的N-钙粘蛋白/连环蛋白复合体。在这项研究中，我们探讨了N-钙粘蛋白功能的抑制是否会影响淀粉样β蛋白诱导的突触损伤。我们发现，无论是通过干扰同型结合的特定多肽，还是通过表达显性阴性的、胞外结构域缺失的N-钙粘蛋白突变体，阻断N-钙粘素功能，都会导致淀粉样β蛋白对培养的皮质神经元突触功能的影响显著加速。AMPA(alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic酸)受体介导的微小兴奋性突触后电流的频率在应用淀粉样β蛋白时比对照组更早地减少。我们进一步假设，在N-钙粘素蛋白降解过程中产生的胞外结构域脱落的跨膜C末端片段可能类似地增强淀粉样β蛋白诱导的突触损伤。事实上，人类N-钙粘蛋白C末端片段1的表达强烈加速了淀粉样β蛋白触发的突触损伤。胞外结构域脱落的N-钙粘蛋白C末端片段1进一步被伽马分泌酶切割。因此，我们利用药物抑制γ-分泌酶和表达显性负性早老素1突变体L166P来增加内源性N-钙粘蛋白C末端片段1的存在。在这些条件下，我们再次发现淀粉样β蛋白诱导的突触损伤有很强的加速作用，这种加速可以通过全长N-钙粘蛋白的过度表达来补偿。有趣的是，对阿尔茨海默病患者死后大脑的蛋白质印迹分析显示，N-钙粘蛋白C-末端片段1的存在增强。因此，蛋白水解性产生的N-钙粘蛋白C-末端片段1对N-钙粘蛋白功能的抑制可能通过加速淀粉样β蛋白触发的突触损伤在阿尔茨海默病的进展中发挥重要作用。
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-beta peptides are well known to induce functional damage, destabilization and loss of brain synapses. However, the complex molecular mechanisms of amyloid-beta 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-beta-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-beta 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-beta 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-beta-induced synapse damage. Indeed, expression of human N-cadherin C-terminal fragment 1 strongly accelerated amyloid-beta-triggered synapse impairment. Ectodomain-shed N-cadherin C-terminal fragment 1 is further proteolytically cleaved by gamma-secretase. Therefore, both pharmacological inhibition of gamma-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-beta-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-beta-triggered synapse damage.