Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease.
Amyloid-β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer's disease.
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DOI：
10.1523/jneurosci.4152-10.2011
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发表时间：
2011-01-12
期刊：
影响因子：
--
通讯作者：
Mucke L
中科院分区：
文献类型：
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作者：
Roberson ED;Halabisky B;Yoo JW;Yao J;Chin J;Yan F;Wu T;Hamto P;Devidze N;Yu GQ;Palop JJ;Noebels JL;Mucke L
阿尔茨海默病(AD)是最常见的神经退行性疾病，是一个日益严重的公共卫生问题，目前仍缺乏有效的治疗方法。最近的证据表明，微管相关蛋白tau可能通过调节酪氨酸激酶Fyn来介导淀粉样蛋白β肽(Aβ)的毒性。我们先前已经证明，tau的减少可以防止Aβ过度表达的人淀粉样前体蛋白(HAPP)转基因小鼠的认知障碍，而Fyn的过度表达会加剧认知障碍。然而，Aβ、tau和Fyn在AD相关发病机制中的协同作用机制仍未完全阐明。在这里，我们研究了这种致病三联体的突触和网络效应。Tau降低可阻止A、β和Fyn的协同作用所致的认知功能下降。Tau的减少也阻止了Happ小鼠的突触传递和可塑性缺陷。使用脑电图法检查网络效应，我们发现tau的减少阻止了多个品系的Happ小鼠的自发癫痫样活动。Tau的减少也降低了Aβ和FYN过度表达的小鼠自发和化学诱导癫痫发作的严重程度。为了更好地了解这些保护作用，我们记录了使用和不使用tau的Happ小鼠急性海马片的全细胞电流。带有tau的HAPP小鼠自发和诱发的兴奋电流增加，抑制电流减少，NMDA受体功能障碍。Tau的减少增加了Happ小鼠的抑制电流和归一化兴奋/抑制平衡和NMDA受体介导的电流。我们的结果表明，Aβ、tau和fyn共同损害突触和网络功能，并提示破坏这些因素之间的共生关系可能对治疗有益。
Alzheimer’s disease (AD), the most common neurodegenerative disorder, is a growing public health problem and still lacks effective treatments. Recent evidence suggests that microtubule-associated protein tau may mediate amyloid-β peptide (Aβ) toxicity by modulating the tyrosine kinase Fyn.Weshowed previously that tau reduction prevents, and Fyn overexpression exacerbates, cognitive deficits in human amyloid precursor protein (hAPP) transgenic mice overexpressing Aβ. However, the mechanisms by which Aβ, tau, and Fyn cooperate in AD-related pathogenesis remain to be fully elucidated. Here we examined the synaptic and network effects of this pathogenic triad. Tau reduction prevented cognitive decline induced by synergistic effects of Aβ and Fyn. Tau reduction also prevented synaptic transmission and plasticity deficits in hAPP mice. Using electroencephalography to examine network effects, we found that tau reduction prevented spontaneous epileptiform activity in multiple lines of hAPP mice. Tau reduction also reduced the severity of spontaneous and chemically induced seizures in mice overexpressing both Aβ and Fyn. To better understand these protective effects, we recorded whole cell currents in acute hippocampal slices from hAPP mice with and without tau. hAPP mice with tau had increased spontaneous and evoked excitatory currents, reduced inhibitory currents, and NMDA receptor dysfunction. Tau reduction increased inhibitory currents and normalized excitation/inhibition balance and NMDA receptor-mediated currents in hAPP mice. Our results indicate that Aβ, tau, and Fyn jointly impair synaptic and network function and suggest that disrupting the copathogenic relationship between these factors could be of therapeutic benefit.