AbstractThe amyloid cascade hypothesis assumes that the development of Alzheimer’s disease (AD) is driven by a self-perpetuating cycle, in which β-amyloid (Aβ) accumulation leads to Tau pathology and neuronal damages. A particular mutation (A673T) of the amyloid precursor protein (APP) was identified among Icelandic population.

摘要淀粉样蛋白级联假说假设阿尔茨海默病（AD）的发展是由一个自我延续的周期驱动的，其中β-淀粉样蛋白（aβ）的积累导致Tau病理和神经元损伤。在冰岛人群中发现了淀粉样前体蛋白（APP）的特定突变（A673T）。

It provides a protective effect against Alzheimer- and age-related cognitive decline. This APP mutation leads to the reduced production of Aβ with A2T (position in peptide sequence) change (Aβice). In addition, Aβice has the capacity to form protective heterodimers in association with wild-type Aβ. Despite the emerging interest in Aβice during the last decade, the impact of Aβice on events associated with the amyloid cascade has never been reported.

它对阿尔茨海默病和年龄相关的认知能力下降具有保护作用。这种APP突变导致A2T（肽序列中的位置）改变（Aβice）导致Aβ产生减少。此外，Aβice具有与野生型Aβ结合形成保护性异二聚体的能力。尽管在过去十年中人们对Aβice产生了兴趣，但从未报道过Aβice对与淀粉样蛋白级联反应相关的事件的影响。

First, the effects of Aβice were evaluated in vitro by electrophysiology on hippocampal slices and by studying synapse morphology in cortical neurons. We showed that Aβice protects against endogenous Aβ-mediated synaptotoxicity. Second, as several studies have outlined that a single intracerebral administration of Aβ can worsen Aβ deposition and cognitive functions several months after the inoculation, we evaluated in vivo the long-term effects of a single inoculation of Aβice or Aβ-wild-type (Aβwt) in the hippocampus of transgenic mice (APPswe/PS1dE9) over-expressing Aβ1-42 peptide.

首先，通过对海马切片的电生理学和研究皮质神经元的突触形态，在体外评估了Aβice的作用。我们发现Aβice可以防止内源性Aβ介导的突触毒性。其次，正如一些研究已经概述的那样，单次脑内注射aβ可以在接种后几个月恶化aβ沉积和认知功能，我们在体内评估了单次接种aβice或aβ-野生型（aβwt）在过量表达aβ1-42肽的转基因小鼠（APPswe/PS1dE9）的海马中的长期作用。

Interestingly, we found that the single intra-hippocampal inoculation of Aβice to mice rescued synaptic density and spatial memory losses four months post-inoculation, compared with Aβwt inoculation. Although Aβ load was not modulated by Aβice infusion, the amount of Tau-positive neuritic plaques was significantly reduced.

有趣的是，我们发现，与Aβwt接种相比，向小鼠单次海马内接种Aβice可以挽救接种后四个月的突触密度和空间记忆损失。尽管Aβ负荷不受Aβ冰输注的调节，但Tau阳性神经炎斑块的数量显着减少。

Finally, a lower phagocytosis by microglia of post-synaptic compounds was detected in Aβice-inoculat.

最后，在aβice接种物中检测到小胶质细胞对突触后化合物的吞噬作用较低。

IntroductionAlzheimer’s disease (AD) is the most widespread cause of dementia in the world. It is characterized by intracerebral accumulation of abnormal proteinaceous assemblies made of amyloid-β (Aβ) peptides and Tau proteins. Aβ peptides arise from the proteolytic cleavage of the amyloid precursor protein (APP), leading to monomers of Aβ that progressively aggregate to form fibrillary Aβ deposits (Aβ plaques) [1].

引言阿尔茨海默病（AD）是世界上痴呆症最广泛的原因。它的特征是由淀粉样蛋白-β（Aβ）肽和Tau蛋白组成的异常蛋白质组装体在脑内积累。Aβ肽来自淀粉样前体蛋白（APP）的蛋白水解切割，导致Aβ单体逐渐聚集形成纤维状Aβ沉积物（Aβ斑块）。

The most common forms of Aβ found in the brain are Aβ1-40 and Aβ1-42 that have 40 and 42 amino acids, respectively. Aβ1-42 is more prone to aggregation than Aβ1-40 [1]. Aβ plaques can be surrounded by hyperphosphorylated Tau aggregates within neurites and are called neuritic plaques. AD is also characterized by a progressive synaptic dysfunction leading to cognitive deficits [2].The whole-genome sequencing of the Icelander population revealed an Icelandic mutation (APPA673T or APPice) which protects against AD [3].

在大脑中发现的最常见的Aβ形式是分别具有40和42个氨基酸的Aβ1-40和Aβ1-42。Aβ1-42比Aβ1-40更容易聚集。Aβ斑块可以被神经突内过度磷酸化的Tau聚集体包围，称为神经炎斑块。AD的特征还在于进行性突触功能障碍导致认知缺陷（2）。冰岛人群体的全基因组测序揭示了一种冰岛突变（APPA673T或APPice），它可以防止AD（3）。

The alanine to threonine substitution in the codon 673 of the APP gene occurs within the Aβ sequence close to the β-secretase cleavage site of the APP. The produced Aβ displays A2T (position in peptide sequence) change. A widely advanced hypothesis to explain the protective effect of this mutation is that it shifts APP processing from the amyloidogenic to the non-amyloidogenic pathway leading to a reduced toxic-Aβ production [3,4,5,6].

APP基因密码子673中的丙氨酸到苏氨酸取代发生在靠近APP的β-分泌酶切割位点的Aβ序列内。产生的Aβ显示A2T（肽序列中的位置）变化。解释这种突变的保护作用的一个广泛提出的假设是，它将APP加工从淀粉样蛋白生成途径转变为非淀粉样蛋白生成途径，从而导致毒性Aβ产生减少[3,4,5,6]。

It has also been suggested that Aβ with Icelandic mutation can form Aβ heterodimers with wild-type Aβ [7] and delay aggregation of Aβ peptides [4]. Despite the emerging interest in Aβ with Icelandic mutation during the last decade, their impacts on synaptic impairments and on events associated with the amyloid cascade have never been reported.Since Aβ is known to induce synaptic deficits [2, 8,9,10,11], the first a.

也有人提出，具有冰岛突变的Aβ可以与野生型Aβ形成Aβ异二聚体，并延迟Aβ肽的聚集。尽管在过去十年中人们对具有冰岛突变的Aβ产生了兴趣，但从未报道过它们对突触损伤和与淀粉样蛋白级联相关的事件的影响。由于已知Aβ会诱导突触缺陷[2,8,9,10,11]，因此第一个A。

To assess the level of « total » Aβ (secreted into the medium or produced in cell lysate), after 72 h infection of cortical neurons with lentivirus producing various APPX mutants we performed an ELISA assay described in Supplementary Materials.Production of recombinant Aβ peptidesRecombinant wild-type human β-amyloid 1–42 protein (Aβwt) and Aβice mutant (A2T) were produced as described in Supplementary Materials.Electrophysiology recordingsHorizontal brain slices containing the somatosensory cortex were prepared from 20 to 30 day-old OF1 mice.

为了评估“总”Aβ（分泌到培养基中或在细胞裂解物中产生）的水平，在用产生各种APPX突变体的慢病毒感染皮质神经元72小时后，我们进行了补充材料中描述的ELISA测定。重组Aβ肽的产生如补充材料中所述，产生了结合野生型人β-淀粉样蛋白1-42蛋白（Aβwt）和Aβice突变体（A2T）的重组Aβ肽。电生理记录从20至30天大的OF1小鼠制备含有体感皮层的水平脑切片。

Stimulating electrodes (bipolar microelectrodes) were placed in the stratum radiatum to stimulate the Schaffer collateral pathway. Field EPSPs (fEPSPs) were recorded in the stratum radiatum. For LTP experiments, test stimuli (0.2 ms pulse width) were delivered once every 15 s and the stimulus intensity was set to give baseline fEPSP slopes that were 50% of maximal evoked slopes.

将刺激电极（双极微电极）放置在辐射层中以刺激Schaffer侧支通路。在辐射层中记录了野外EPSP（fEPSP）。对于LTP实验，每15秒传递一次测试刺激（0.2 ms脉冲宽度），并设置刺激强度以给出基线fEPSP斜率，其为最大诱发斜率的50%。

Slices that showed maximal fEPSP sizes <1 mV were rejected. Long-term potentiation (LTP) in the hippocampal CA1 region was induced by delivering two 100 Hz protocols (2 × 100 Hz) with an interval of 20 s to the Schaffer collateral/commissural pathway. Aβ peptides were added to the ACSF bath (final concentration of Aβ: 100 nM) 15 min prior to recording.

显示最大fEPSP大小<1mV的切片被拒绝。通过向Schaffer侧支/连合通路递送两个间隔为20秒的100 Hz方案（2×100 Hz），诱导海马CA1区的长时程增强（LTP）。记录前15分钟，将Aβ肽添加到ACSF浴中（Aβ的终浓度：100 nM）。

2 × 100 Hz was delivered after 15 min of stable baseline (see Supplementary Materials).Transgenic mice, stereotaxic surgery and behavioral evaluationsIn vivo experiments involved the APPswe/PS1dE9 mouse model of amyloidosis (C57Bl/6 background) [23, 24]. Aβ plaques can be detected as early as 4 months of age in these mice and increase in number and total area with age [23].

稳定基线15分钟后交付2×100 Hz（见补充材料）。转基因小鼠，立体定向手术和行为评估在体内实验中涉及淀粉样变性的APPswe/PS1dE9小鼠模型（C57Bl/6背景）[23，24]。在这些小鼠中，早在4个月大时就可以检测到Aβ斑块，并且随着年龄的增长，斑块的数量和总面积都会增加（23）。

This model expresses endogenous murine Tau protein isoforms and is not transgenic for any human Tau. Two-month-old mice received bilater.

该模型表达内源性鼠Tau蛋白同工型，对于任何人类Tau都不是转基因的。两个月大的小鼠接受了双层。

Data availability

数据可用性

The data that support the findings of this study are available from the corresponding author, upon request.

支持本研究结果的数据可应要求从通讯作者处获得。

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Download referencesAcknowledgementsWe thank Martine Guillermier and Mylène Gaudin for surgical expertise. We thank Marie Maechling for assistance in the revision of the article. We thank Nicolas Heck for his help in synapse quantification. The project was funded by the Fondation Vaincre Alzheimer and the Association France-Alzheimer.

下载参考文献致谢我们感谢Martine Guillermier和Mylène Gaudin的外科专业知识。我们感谢玛丽·梅奇林（MarieMachling）在修订文章方面的帮助。我们感谢尼古拉斯·赫克（NicolasHeck）在突触量化方面的帮助。该项目由Vaincre阿尔茨海默病基金会和法国阿尔茨海默病协会资助。

It was performed in a core facility supported by/member of NeurATRIS-ANR-11-INBS-0011. MC was financed by the French Ministère de l’Enseignement Supérieure, de la Recherche et de l’Innovation.Author informationAuthors and AffiliationsUniversité Paris-Saclay, CEA, CNRS, Laboratoire des Maladies Neurodégénératives, 18 Route du Panorama, F-92265, Fontenay-aux-Roses, FranceMarina Célestine, Fanny Petit, Luc Bousset, Anne-Sophie Hérard & Marc DhenainCommissariat à l’Energie Atomique et aux Energies Alternatives (CEA), Direction de la Recherche Fondamentale (DRF), Institut de Biologie François Jacob, MIRCen, 18 Route du Panorama, F-92265, Fontenay-aux-Roses, FranceMarina Célestine, Fanny Petit, Luc Bousset, Anne-Sophie Hérard & Marc DhenainUniv.

它是在Neuratris-ANR-11-INBS-0011成员支持的核心设施中执行的。MC由法国高等教育、研究和创新部资助。作者信息作者和附属机构巴黎萨克莱大学，CEA，CNRS，神经退行性疾病实验室，18全景路线，F-92265，Fontenay aux Roses，Francemarina Célestine，Fanny Petit，Luc Bousset，Anne-Sophie Hérard&Marc Dhenain原子能和替代能源委员会（CEA），基础研究方向（DRF），生物研究所François Jacob，MIRCEN，18全景路线，F-92 265，Fontenay aux Roses，Francemarina Célestine、Fanny Petit、Luc Bousset、Anne-Sophie Hérard和Marc Dhenainuniv。

Grenoble Alpes, Inserm, U1216, Grenoble Institut Neurosciences, GIN, 38000, Grenoble, FranceMuriel Jacquier-Sarlin, Eve Borel, Fabien Lante & Alain BuissonAuthorsMarina CélestineView author publicationsYou can also search for this author in.

格勒诺布尔阿尔卑斯，Inserm，U1216，格勒诺布尔神经科学研究所，GIN，38000，格勒诺布尔，FranceMuriel Jacquier Sarlin，Eve Borel，Fabien Lante＆Alain BuissonAuthorsMarina CélestineView作者出版物您也可以在中搜索这位作者。

PubMed Google ScholarMuriel Jacquier-SarlinView author publicationsYou can also search for this author in

PubMed Google Scholarmauriel Jacquier SarlinView作者出版物您也可以在

PubMed Google ScholarEve BorelView author publicationsYou can also search for this author in

PubMed谷歌学术评论BorelView作者出版物您也可以在

PubMed Google ScholarFanny PetitView author publicationsYou can also search for this author in

PubMed Google ScholarFanny PetitView作者出版物您也可以在

PubMed Google ScholarFabien LanteView author publicationsYou can also search for this author in

PubMed谷歌学者Fabien LanteView作者出版物您也可以在

PubMed Google ScholarLuc BoussetView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsMC, ASH, AB, and MD. contributed to the study conception and design. MJS, EB, AB produced the recombinant Aβ proteins. MC, LB performed Thioflavin aggregation assays and electron microscopy. MJS, EB, AB performed ex vivo experiments on cell cultures.

PubMed谷歌学术贡献SMC，ASH，AB和MD.为研究概念和设计做出了贡献。MJS，EB，AB产生重组Aβ蛋白。MC，LB进行了硫黄素聚集测定和电子显微镜检查。MJS，EB，AB对细胞培养物进行了离体实验。

FL, AB performed electrophysiology studies. MC performed the inoculations in mice. MC designed and performed memory evaluations, MC, ASH, FP, MD designed and performed the immunohistological analysis in animals. MC, MJS, and AB performed biochemical analysis. MC, AB, and MD wrote the manuscript. All authors commented on previous versions of the manuscript.

FL，AB进行了电生理学研究。MC在小鼠中进行接种。MC设计并进行了记忆评估，MC，ASH，FP，MD设计并进行了动物免疫组织学分析。MC，MJS和AB进行了生化分析。MC，AB和MD撰写了手稿。所有作者都对稿件的以前版本发表了评论。

All authors read and approved the final manuscript.Corresponding authorCorrespondence to.

所有作者都阅读并批准了最终手稿。对应作者对应。

Marc Dhenain.Ethics declarations

马克·德纳因。道德宣言

Competing interests

相互竞争的利益

The authors declare no competing interests.

作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleCélestine, M., Jacquier-Sarlin, M., Borel, E. et al. Transmissible long-term neuroprotective and pro-cognitive effects of 1–42 beta-amyloid with A2T icelandic mutation in an Alzheimer’s disease mouse model.

转载和许可本文引用本文Célestine，M.，Jacquier-Sarlin，M.，Borel，E。等人。阿尔茨海默病小鼠模型中具有A2T冰岛突变的1-42β淀粉样蛋白的可传播长期神经保护和促认知作用。

Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02611-8Download citationReceived: 29 July 2023Revised: 10 May 2024Accepted: 14 May 2024Published: 14 June 2024DOI: https://doi.org/10.1038/s41380-024-02611-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

摩尔精神病学（2024）。https://doi.org/10.1038/s41380-024-02611-8Download收到引文日期：2023年7月29日修订日期：2024年5月10日接受日期：2024年5月14日发布日期：2024年6月14日OI：https://doi.org/10.1038/s41380-024-02611-8Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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神经科学生理学