Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of MOH, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China.
Department of Neurobiology, Institute of Neuroscience, Key Laboratory of Medical Neurobiology of MOH, Key Laboratory of Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, China; Children's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China.
Neurobiol Dis. 2017 Oct;106:171-180. doi: 10.1016/j.nbd.2017.07.001. Epub 2017 Jul 4.
Accumulation of amyloid β (Aβ) induces neuronal, synaptic, and cognitive deficits in patients and animal models of Alzheimer's disease (AD). The underlying mechanisms, however, remain to be fully elucidated. In the present study, we found that Aβ interacted with ErbB4, a member of the receptor tyrosine kinase family and mainly expressed in GABAergic interneurons. Deleting ErbB4 in parvalbumin-expressing neurons (PV neurons) significantly attenuated oligomeric Aβ-induced suppression of long term potentiation (LTP). Furthermore, specific ablation of ErbB4 in PV neurons via Cre/loxP system greatly improved spatial memory and synaptic plasticity in the hippocampus of hAPP-J20 mice. The deposition of Aβ detected by 3D6 and Thioflavin S staining and the proteolytic processing of hAPP analyzed by western blotting were not affected in the hippocampus of hAPP-J20 mice by deleting ErbB4 in PV neurons. Our data suggested that ErbB4 in PV neurons mediated Aβ-induced synaptic and cognitive dysfunctions without affecting Aβ levels.
淀粉样蛋白 β（Aβ）的积累会导致阿尔茨海默病（AD）患者和动物模型中的神经元、突触和认知功能障碍。然而，其潜在机制仍有待充分阐明。在本研究中，我们发现 Aβ与 ErbB4 相互作用，ErbB4 是受体酪氨酸激酶家族的成员，主要表达于 GABA 能中间神经元。在表达 Parvalbumin 的神经元（PV 神经元）中敲除 ErbB4 可显著减轻寡聚体 Aβ诱导的长时程增强（LTP）抑制。此外，通过 Cre/loxP 系统特异性敲除 PV 神经元中的 ErbB4 可显著改善 hAPP-J20 小鼠海马体的空间记忆和突触可塑性。通过在 PV 神经元中敲除 ErbB4 ，并未影响 hAPP-J20 小鼠海马体中 Aβ的沉积（由 3D6 和 Thioflavin S 染色检测）和 hAPP 的蛋白水解加工（通过 Western blot 分析）。我们的数据表明，PV 神经元中的 ErbB4 介导了 Aβ诱导的突触和认知功能障碍，而不影响 Aβ水平。
