Fyn inhibition rescues established memory and synapse loss in Alzheimer mice.
Fyn inhibition rescues established memory and synapse loss in Alzheimer mice.
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DOI：
10.1002/ana.24394
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发表时间：
2015-06
影响因子：
11.2
通讯作者：
Strittmatter, Stephen M.
中科院分区：
文献类型：
--
作者：
Kaufman, Adam C.;Salazar, Santiago V.;Haas, Laura T.;Yang, Jinhee;Kostylev, Mikhail A.;Jeng, Amanda T.;Robinson, Sophie A.;Gunther, Erik C.;van Dyck, Christopher H.;Nygaard, Haakon B.;Strittmatter, Stephen M.
目前尚无有效的疾病调节剂可用于治疗 AD。 Fyn 酪氨酸激酶与淀粉样蛋白-β 寡聚物 (Aβo) 引发并由 Tau 传播的阿尔茨海默病 (AD) 病理有关。因此，Fyn 抑制可以预防或延缓疾病进展。在这里，我们试图将 Src 家族激酶抑制剂肿瘤化合物 AZD0530 重新用于治疗 AD。在小鼠中评估了 AZD0530 的药代动力学和分布。通过脑切片测定测试了 AZD0530 对 Fyn、Pyk2 和 Glu 受体的 Aβo 信号传导的抑制。对野生型和 AD 转基因小鼠进行 AZD0530 或媒介物处理后，通过 Morris 水迷宫和新物体识别来评估记忆力。对于这些队列，通过免疫组织化学和免疫印迹研究了 APP 代谢、突触标记物（SV2 和 PSD-95）以及 Fyn 靶点（Pyk2 和 Tau）。 AZD0530 有效抑制 Fyn，并阻止 Aβo 诱导的 Fyn 信号传导以及 AD 风险基因产物 Pyk2 和脑切片中 NR2B Glu 受体的下游磷酸化。治疗 4 周后，APP/PS1 转基因小鼠的 AZD0530 给药完全挽救了空间记忆缺陷和突触耗竭，且不改变 APP 或 Aβ 代谢。 AZD0530 治疗还可减少 APP/PS1 小鼠中的小胶质细胞活化，并挽救 APP/PS1/Tau 转基因小鼠中的 Tau 磷酸化和沉积异常。没有证据表明 AZD0530 有慢性毒性。靶向 Fyn 可以逆转 AD 小鼠模型中发现的记忆缺陷，并挽救该疾病的突触密度损失特征。因此，AZD0530 是一个有前途的候选药物，可以作为 AD 的潜在疗法进行测试。
Currently no effective disease modifying agents exist for the treatment of AD. The Fyn tyrosine kinase is implicated in Alzheimer’s disease (AD) pathology triggered by amyloid-β oligomers (Aβo) and propagated by Tau. Thus, Fyn inhibition may prevent or delay disease progression. Here, we sought to repurpose the Src family kinase inhibitor oncology compound, AZD0530, for AD. The pharmacokinetics and distribution of AZD0530 were evaluated in mice. Inhibition of Aβo signaling to Fyn, Pyk2 and Glu receptors by AZD0530 was tested by brain slice assays. After AZD0530 or vehicle treatment of wild type and AD transgenic mice, memory was assessed by Morris water maze and novel object recognition. For these cohorts, APP metabolism, synaptic markers (SV2 and PSD-95), and targets of Fyn (Pyk2 and Tau) were studied by immunohistochemistry and by immunoblotting. AZD0530 potently inhibits Fyn and prevents both Aβo-induced Fyn signaling and downstream phosphorylation of the AD risk gene product, Pyk2, and of NR2B Glu receptors in brain slices. After 4 weeks of treatment, AZD0530 dosing of APP/PS1 transgenic mice fully rescues spatial memory deficits and synaptic depletion, without altering APP or Aβ metabolism. AZD0530 treatment also reduces microglial activation in APP/PS1 mice, and rescues Tau phosphorylation and deposition abnormalities in APP/PS1/Tau transgenic mice. There is no evidence of AZD0530 chronic toxicity. Targeting Fyn can reverse memory deficits found in AD mouse models, and rescue synapse density loss characteristic of the disease. Thus, AZD0530 is a promising candidate to test as a potential therapy for AD.
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影响因子：
3.1
作者：
Gucalp A;Sparano JA;Caravelli J;Santamauro J;Patil S;Abbruzzi A;Pellegrino C;Bromberg J;Dang C;Theodoulou M;Massague J;Norton L;Hudis C;Traina TA
通讯作者：
Traina TA
影响因子：
16.6
作者：
Freir, Darragh B.;Nicoll, Andrew J.;Klyubin, Igor;Panico, Silvia;Mc Donald, Jessica M.;Risse, Emmanuel;Asante, Emmanuel A.;Farrow, Mark A.;Sessions, Richard B.;Saibil, Helen R.;Clarke, Anthony R.;Rowan, Michael J.;Walsh, Dominic M.;Collinge, John
通讯作者：
Collinge, John
DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
DOI：
10.1523/jneurosci.4992-08.2010
发表时间：
2010-01-13
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Bartos JA;Ulrich JD;Li H;Beazely MA;Chen Y;Macdonald JF;Hell JW
通讯作者：
Hell JW
影响因子：
3.4
作者：
Gangadhar, Tara C.;Clark, Joseph I.;Gajewski, Thomas F.
通讯作者：
Gajewski, Thomas F.