AGING CELL:川大团队发现,长寿基因Klotho可改善阿尔茨海默病中Aβ的清除和认知

2020-09-22 haibei MedSci原创

阿尔茨海默病(AD)是一种以老年斑块沉积、细胞内神经纤维缠结和进行性认知功能下降为主要特征的慢性年龄相关性神经退行性疾病。截至2018年,全球已诊断出超过5000万例AD患者。

阿尔茨海默病(AD)是一种以老年斑块沉积、细胞内神经纤维缠结和进行性认知功能下降为主要特征的慢性年龄相关性神经退行性疾病。截至2018年,全球已诊断出超过5000万例AD患者。人们提出了多种假说来解释阿尔茨海默病的病因和发病机制。淀粉样蛋白-β(Aβ)级联假说是过去二十年来解释AD发病机制的主流假说。在AD患者的大脑中观察到Aβ肽的产生和清除失衡,随后形成淀粉样蛋白斑块,并导致神经元功能障碍。

Aβ清除不足,而非Aβ过度生成,被认为是一个主要的致病因素,而Aβ过度生成又可能引发神经炎症、进行性突触丧失,最终导致认知能力下降。研究表明,Aβ激活NACHT、LRR和含PYD域的蛋白3(NLRP3)炎症体,介导小胶质细胞从M2型转变为M1型,减少Aβ的清除。因此,Aβ和NLRP3炎症体的激活之间形成了一个恶性反馈环,导致患者病情逐渐恶化。

外排转运体(如:低密度脂蛋白受体相关蛋白1[LRP1]、P-糖蛋白[P-gp]和三磷酸腺苷[ATP]结合盒转运体A1[ABCA1])和晚期糖化终产物的内排转运体受体(RAGE)的表达或活性的改变在AD患者和小鼠模型中被观察到,导致Aβ的清除障碍。抑制NLRP3/caspase-1轴,增强转运体介导的Aβ清除,理论上可以预防AD的发生。

已有的研究显示,抗衰老基因Klotho在肾脏和脉络丛中高表达,在脑实质中表达较低。Klotho具有多种生理功能,如抗神经炎症作用和调节自噬作用。

以往的研究表明,AD患者和小鼠模型中脑内的Klotho明显低于年龄匹配的健康群体。更多的研究提供了Klotho可能缓解一系列神经退行性疾病的迹象。这些研究结果提供了令人信服的证据,证明Klotho可能是AD的新型治疗靶点。

在以前的一项研究中,研究人员在7个月大的淀粉样前体蛋白/resenilin 1(APP/PS1)小鼠模型中维持脑内Klotho上调长达3个月,这显著降低了Aβ水平,减轻了认知功能障碍。然而,至今为止,长期Klotho上调对AD晚期的影响和潜在机制仍不清楚。

基于积累的Klotho抗AD作用的证据,来自四川大学的研究人员推测,Klotho通过促进小胶质细胞从M1型向M2型转化,调节Aβ转运体功能,从而改善Aβ病理和认知功能障碍。

为了验证这一假设,研究人员通过在大脑侧脑室注射携带全长小鼠Klotho cDNA的慢病毒,诱导13月龄APP/PS1小鼠脑内Klotho的过表达。

之后,研究人员探究了Klotho过表达对小鼠认知、Aβ负担、Aβ相关神经病理、小胶质细胞转化和Aβ运输系统的影响。此外,研究人员通过敲除原代人脉络丛上皮细胞(HCPEpiCs)中的Klotho,研究了Klotho对血-脑脊液屏障处Aβ转运的影响。

结果显示,大脑和血清中Klotho水平的上调显著改善了老年APP/PS1小鼠的Aβ负担、神经元和突触损失,以及认知障碍。Klotho治疗能显著抑制NACHT、LRR和含PYD域蛋白3(NLRP3),以及导致随后小胶质细胞向M2型的转化,这可能会增强小胶质细胞介导的Aβ清除。

同时,Klotho过表达也调节了Aβ转运体的表达,可能促进Aβ转运体介导的Aβ清除。此外,Klotho敲除后,HCPEpiCs体外转运Aβ的能力也明显受损。

鉴于Klotho过表达的神经保护作用,本研究结果表明,应进一步研究Klotho作为AD的治疗靶点的潜力。

 

原始出处:

Yue Zhao et al. Klotho overexpression improves amyloid‐β clearance and cognition in the APP/PS1 mouse model of Alzheimer's disease. AGING CELL (2020). DOI: https://doi.org/10.1111/acel.13239

 

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    2021-02-09 爆笑小医
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  5. [GetPortalCommentsPageByObjectIdResponse(id=1871986, encodeId=30a718e198641, content=<a href='/topic/show?id=fd764459a8' target=_blank style='color:#2F92EE;'>#Cell#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=35, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4459, encryptionId=fd764459a8, topicName=Cell)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=524d95, createdName=zhaozhouchifen, createdTime=Sat Jun 19 18:30:35 CST 2021, time=2021-06-19, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1818058, encodeId=11c51818058cf, content=<a href='/topic/show?id=4c9f9e777ac' target=_blank style='color:#2F92EE;'>#阿尔茨海#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97777, encryptionId=4c9f9e777ac, topicName=阿尔茨海)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=636e2500187, createdName=12498da4m32(暂无昵称), createdTime=Fri Mar 12 00:30:35 CST 2021, time=2021-03-12, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1962287, encodeId=9367196228e37, content=<a href='/topic/show?id=dbe6445416' target=_blank style='color:#2F92EE;'>#CEL#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=36, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=4454, encryptionId=dbe6445416, topicName=CEL)], attachment=null, authenticateStatus=null, createdAvatar=, createdBy=395f25, createdName=爆笑小医, createdTime=Tue Feb 09 00:30:35 CST 2021, time=2021-02-09, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1817035, encodeId=f7cf181e03592, content=<a href='/topic/show?id=17b59e77626' target=_blank style='color:#2F92EE;'>#阿尔茨#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=26, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97776, encryptionId=17b59e77626, topicName=阿尔茨)], attachment=null, authenticateStatus=null, createdAvatar=https://thirdwx.qlogo.cn/mmopen/vi_32/Bnia2EtH2IvyBtniaWHPQOYAicsN3IAL1ZuPV7qyALcdCiawRJdEiafMxWTxzERQW7eeKg8HfCKCRK2CJicy073C4RJg/132, createdBy=464b2500186, createdName=ms1948154235210413, createdTime=Wed Apr 07 22:30:35 CST 2021, time=2021-04-07, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1407824, encodeId=983c140e82444, content=<a href='/topic/show?id=ab471053548' target=_blank style='color:#2F92EE;'>#Klotho#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=37, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=10535, encryptionId=ab471053548, topicName=Klotho)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=74062724030, createdName=drj2004, createdTime=Wed Sep 23 22:30:35 CST 2020, time=2020-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1470412, encodeId=5c1314e041290, content=<a href='/topic/show?id=45a79e7788c' target=_blank style='color:#2F92EE;'>#阿尔茨海默#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=21, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=97778, encryptionId=45a79e7788c, topicName=阿尔茨海默)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=21015, createdName=heli0118, createdTime=Wed Sep 23 22:30:35 CST 2020, time=2020-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1512102, encodeId=d12015121028e, content=<a href='/topic/show?id=e55a9690677' target=_blank style='color:#2F92EE;'>#长寿基因#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=30, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=96906, encryptionId=e55a9690677, topicName=长寿基因)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=0f4f10440290, createdName=ms691033630344116, createdTime=Wed Sep 23 22:30:35 CST 2020, time=2020-09-23, status=1, ipAttribution=), GetPortalCommentsPageByObjectIdResponse(id=1605270, encodeId=e64d16052e0f8, content=<a href='/topic/show?id=b820309108' target=_blank style='color:#2F92EE;'>#Aβ#</a>, beContent=null, objectType=article, channel=null, level=null, likeNumber=31, replyNumber=0, topicName=null, topicId=null, topicList=[TopicDto(id=3091, encryptionId=b820309108, topicName=Aβ)], attachment=null, authenticateStatus=null, createdAvatar=null, createdBy=ee1c19366172, createdName=膀胱癌, createdTime=Wed Sep 23 22:30:35 CST 2020, time=2020-09-23, status=1, ipAttribution=)]
    2020-09-23 drj2004
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    2020-09-23 膀胱癌

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