TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice.
TrkB reduction exacerbates Alzheimer's disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice.
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DOI：
10.1038/tp.2015.55
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发表时间：
2015-05-05
影响因子：
6.8
通讯作者：
Ohno M
中科院分区：
文献类型：
--
作者：
Devi L;Ohno M
越来越多的证据表明，脑源性神经营养因子 (BDNF) 及其受体原肌球蛋白相关激酶 B (TrkB) 在阿尔茨海默病 (AD) 早期显着减少。然而，目前尚不清楚 BDNF/TrkB 减少是否可能在机制上参与 AD 的发病机制。为了解决这个问题，我们生成了杂合 TrkB 敲除 (TrkB+/–·5XFAD) 的 5XFAD 转基因小鼠，并在该小鼠模型的早期阶段测试了 TrkB 减少对 AD 样特征的影响，该模型仅显示适度的淀粉样蛋白-β (Aβ) 病理学并保留正常的助记功能。通过海马依赖性自发交替 Y 迷宫任务评估，TrkB+/– 减少加剧了 4-5 月龄 5XFAD 小鼠的记忆力下降，而 TrkB+/– 小鼠的记忆表现并未受到影响。与此同时，TrkB+/–·5XFAD 小鼠的筑巢能力正常，这是一种广泛使用的社会行为测量方法，表明 AD 相关行为障碍的记忆特异性恶化。我们发现 TrkB+/–·5XFAD 和 5XFAD 对照小鼠在脑斑块负荷、Aβ 浓度（包括总 Aβ42 和可溶性寡聚体）以及淀粉样前体蛋白的 β-淀粉样蛋白生成加工方面没有差异。有趣的是，在 TrkB+/–·5XFAD 小鼠中观察到 AMPA/NMDA 谷氨酸受体亚基的海马表达减少，以及 TrkB 下游信号通路受损，例如 CREB（cAMP 反应元件结合蛋白）和 Akt/GSK-3β（糖原合酶激酶-3β），但在 5XFAD 小鼠中没有观察到。在这些信号传导异常中，只有 Akt/GSK-3β 功能障碍发生在 TrkB+/– 小鼠中，而其他信号异常则是 TrkB+/–·5XFAD 小鼠中 TrkB 减少与 Aβ 阈下水平之间的协同后果。总的来说，我们的结果表明，TrkB 减少不会影响 β-淀粉样变性，但会加剧 AD 早期海马记忆和信号传导功能障碍的表现。
Accumulating evidence shows that brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) significantly decrease early in Alzheimer's disease (AD). However, it remains unclear whether BDNF/TrkB reductions may be mechanistically involved in the pathogenesis of AD. To address this question, we generated 5XFAD transgenic mice with heterozygous TrkB knockout (TrkB+/–·5XFAD), and tested the effects of TrkB reduction on AD-like features in this mouse model during an incipient stage that shows only modest amyloid-β (Aβ) pathology and retains normal mnemonic function. TrkB+/– reduction exacerbated memory declines in 5XFAD mice at 4–5 months of age as assessed by the hippocampus-dependent spontaneous alternation Y-maze task, while the memory performance was not affected in TrkB+/– mice. Meanwhile, TrkB+/–·5XFAD mice were normal in nest building, a widely used measure for social behavior, suggesting the memory-specific aggravation of AD-associated behavioral impairments. We found no difference between TrkB+/–·5XFAD and 5XFAD control mice in cerebral plaque loads, Aβ concentrations including total Aβ42 and soluble oligomers and β-amyloidogenic processing of amyloid precursor protein. Interestingly, reductions in hippocampal expression of AMPA/NMDA glutamate receptor subunits as well as impaired signaling pathways downstream to TrkB such as CREB (cAMP response element-binding protein) and Akt/GSK-3β (glycogen synthase kinase-3β) were observed in TrkB+/–·5XFAD mice but not in 5XFAD mice. Among these signaling aberrations, only Akt/GSK-3β dysfunction occurred in TrkB+/– mice, while others were synergistic consequences between TrkB reduction and subthreshold levels of Aβ in TrkB+/–·5XFAD mice. Collectively, our results indicate that reduced TrkB does not affect β-amyloidosis but exacerbates the manifestation of hippocampal mnemonic and signaling dysfunctions in early AD.
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