Ca_V2.1 mediates presynaptic dysfunction induced by amyloid β oligomers.

IF 6.9 1区生物学 Q1 CELL BIOLOGY Cell reports Pub Date : 2025-04-22 Epub Date: 2025-03-23 DOI:10.1016/j.celrep.2025.115451

Alexander F Jeans, Zahid Padamsey, Helen Collins, William Foster, Sally Allison, Steven Dierksmeier, William L Klein, Arn M J M van den Maagdenberg, Nigel J Emptage

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Abstract

Synaptic dysfunction is an early pathological phenotype of Alzheimer's disease (AD) that is initiated by oligomers of amyloid β peptide (Aβ_os). Treatments aimed at correcting synaptic dysfunction could be beneficial in preventing disease progression, but mechanisms underlying Aβ_o-induced synaptic defects remain incompletely understood. Here, we uncover an epithelial sodium channel (ENaC) - Ca_V2.3 - protein kinase C (PKC) - glycogen synthase kinase-3β (GSK-3β) signal transduction pathway that is engaged by Aβ_os to enhance presynaptic Ca_V2.1 voltage-gated Ca²⁺ channel activity, resulting in pathological potentiation of action-potential-evoked synaptic vesicle exocytosis. We present evidence that the pathway is active in human APP transgenic mice in vivo and in human AD brains, and we show that either pharmacological Ca_V2.1 inhibition or genetic Ca_V2.1 haploinsufficiency is sufficient to restore normal neurotransmitter release. These findings reveal a previously unrecognized mechanism driving synaptic dysfunction in AD and identify multiple potentially tractable therapeutic targets.

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CaV2.1介导β淀粉样蛋白低聚物诱导的突触前功能障碍。

突触功能障碍是阿尔茨海默病（AD）的一种早期病理表型，由淀粉样β肽（a - βos）寡聚物引发。旨在纠正突触功能障碍的治疗可能有助于预防疾病进展，但a βo诱导的突触缺陷的机制仍不完全清楚。在这里，我们揭示了上皮钠通道(ENaC) - CaV2.3 -蛋白激酶C (PKC) -糖原合成酶激酶3β (GSK-3β)信号转导途径，该途径由Aβos参与，以增强突触前CaV2.1电压门控Ca2+通道活性，导致动作电位诱发的突触囊泡胞外分泌的病理增强。我们提供的证据表明，该途径在人APP转基因小鼠体内和人AD大脑中是活跃的，并且我们表明药理学CaV2.1抑制或遗传CaV2.1单倍不足足以恢复正常的神经递质释放。这些发现揭示了一个以前未被认识的驱动AD突触功能障碍的机制，并确定了多个潜在的可处理的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell reports CELL BIOLOGY-

CiteScore

13.80

自引率

1.10%

发文量

1305

审稿时长

77 days

期刊介绍： Cell Reports publishes high-quality research across the life sciences and focuses on new biological insight as its primary criterion for publication. The journal offers three primary article types: Reports, which are shorter single-point articles, research articles, which are longer and provide deeper mechanistic insights, and resources, which highlight significant technical advances or major informational datasets that contribute to biological advances. Reviews covering recent literature in emerging and active fields are also accepted. The Cell Reports Portfolio includes gold open-access journals that cover life, medical, and physical sciences, and its mission is to make cutting-edge research and methodologies available to a wide readership. The journal's professional in-house editors work closely with authors, reviewers, and the scientific advisory board, which consists of current and future leaders in their respective fields. The advisory board guides the scope, content, and quality of the journal, but editorial decisions are independently made by the in-house scientific editors of Cell Reports.