Wolframin-1-expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory in mice.
Wolframin-1-expressing neurons in the entorhinal cortex propagate tau to CA1 neurons and impair hippocampal memory in mice.
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DOI：
10.1126/scitranslmed.abe8455
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发表时间：
2021-09-15
影响因子：
17.1
通讯作者：
Ikezu T
中科院分区：
文献类型：
--
作者：
Delpech JC;Pathak D;Varghese M;Kalavai SV;Hays EC;Hof PR;Johnson WE;Ikezu S;Medalla M;Luebke JI;Ikezu T
异常磷酸化的tau蛋白是阿尔茨海默病（AD）的早期神经病理标志物，它首先发生在大脑的内嗅皮层II层（ECII），然后扩散到海马的CA1区。旨在概括这一现象的tau繁殖动物模型大多显示tau从ECII星状神经元转移到齿状回，但直到阿尔茨海默病晚期才出现齿状回的tau病理。表达wolframin -1 （Wfs1+）的锥体神经元在功能上调节小鼠海马CA1神经元。在这里，我们报道了Wfs1+锥体神经元在死后人脑组织的ECII中是保守的，并且Wfs1与早期AD患者大脑中异常磷酸化的tau共定位。Wfs1+神经元特异性表达人P301L突变tau在小鼠ECII中导致tau向海马CA1锥体神经元转移，提示在AD的早期Braak阶段观察到的tau病理扩散。在ECII脑区特异性表达人类突变tau的小鼠中，CA1锥体神经元的电生理记录显示兴奋性降低。光刺激Wfs1+ ECII轴突的多电极阵列记录导致CA1神经元放电减少。CA1锥体神经元的化学发生激活显示CA1中c-fos+细胞的减少。最后，一项恐惧条件反射任务揭示了过度表达人类突变tau的小鼠在ECII中的痕量和情境记忆缺陷。这项工作证明了tau蛋白在小鼠大脑中从ECII转移到CA1，并提供了AD的早期Braak期临床前模型。小鼠大脑内嗅皮层wolframin -1阳性神经元向海马CA1区传播tau蛋白，导致记忆障碍。在阿尔茨海默病的早期阶段，在大脑的内嗅皮层II层（ECII）中观察到异常磷酸化的tau，并从那里扩散到海马CA1区域。在这里，Delpech等人开发了一个动物模型，概括了这种早期tau扩散病理。他们发现，在小鼠大脑ECII的wolframin -1阳性神经元中特异性表达人类突变tau可导致tau特异性转移到海马CA1区。这伴有记忆障碍和CA1锥体神经元活性降低，表明该神经元通路应在阿尔茨海默病中进一步研究。
Abnormally phosphorylated tau, an early neuropathologic marker of Alzheimer’s disease (AD), first occurs in the brain’s entorhinal cortex layer II (ECII) and then spreads to the CA1 field of the hippocampus. Animal models of tau propagation aiming to recapitulate this phenomenon mostly show tau transfer from ECII stellate neurons to the dentate gyrus, but tau pathology in the dentate gyrus does not appear until advanced stages of AD. Wolframin-1–expressing (Wfs1+) pyramidal neurons have been shown functionally to modulate hippocampal CA1 neurons in mice. Here, we report that Wfs1+ pyramidal neurons are conserved in the ECII of postmortem human brain tissue and that Wfs1 colocalized with abnormally phosphorylated tau in brains from individuals with early AD. Wfs1+ neuron–specific expression of human P301L mutant tau in mouse ECII resulted in transfer of tau to hippocampal CA1 pyramidal neurons, suggesting spread of tau pathology as observed in the early Braak stages of AD. In mice expressing human mutant tau specifically in the ECII brain region, electrophysiological recordings of CA1 pyramidal neurons showed reduced excitability. Multielectrode array recordings of optogenetically stimulated Wfs1+ ECII axons resulted in reduced CA1 neuronal firing. Chemogenetic activation of CA1 pyramidal neurons showed a reduction in c-fos+ cells in the CA1. Last, a fear conditioning task revealed deficits in trace and contextual memory in mice overexpressing human mutant tau in the ECII. This work demonstrates tau transfer from the ECII to CA1 in mouse brain and provides an early Braak stage preclinical model of AD. Wolframin-1–positive neurons in the entorhinal cortex of mouse brain propagate tau to the hippocampal CA1 region resulting in memory impairment. Abnormally phosphorylated tau has been observed in the entorhinal cortex layer II (ECII) of the brain and from there spreads to the hippocampal CA1 region during the early stages of Alzheimer’s disease. Here, Delpech et al. develop an animal model that recapitulates this early tau spreading pathology. They show that expressing human mutant tau specifically in Wolframin-1–positive neurons of the ECII of mouse brain resulted in transfer of tau specifically to the hippocampal CA1 area. This was accompanied by memory impairment and reduced activity of CA1 pyramidal neurons, suggesting that this neuronal pathway should be investigated further in Alzheimer’s disease.
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影响因子：
2.5
作者：
BEALL, MJ;LEWIS, DA
通讯作者：
LEWIS, DA
DOI：
10.1126/science.1247485
发表时间：
2014-02-21
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Lovett-Barron M;Kaifosh P;Kheirbek MA;Danielson N;Zaremba JD;Reardon TR;Turi GF;Hen R;Zemelman BV;Losonczy A
通讯作者：
Losonczy A
影响因子：
15.1
作者：
Clayton K;Delpech JC;Herron S;Iwahara N;Ericsson M;Saito T;Saido TC;Ikezu S;Ikezu T
通讯作者：
Ikezu T
影响因子：
16.2
作者：
Fuchs EC;Neitz A;Pinna R;Melzer S;Caputi A;Monyer H
通讯作者：
Monyer H
影响因子：
3.7
作者：
Harris JA;Koyama A;Maeda S;Ho K;Devidze N;Dubal DB;Yu GQ;Masliah E;Mucke L
通讯作者：
Mucke L