Seabrook G R, Smith D W, Bowery B J, Easter A, Reynolds T, Fitzjohn S M, Morton R A, Zheng H, Dawson G R, Sirinathsinghji D J, Davies C H, Collingridge G L, Hill R G
Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK.
Neuropharmacology. 1999 Mar;38(3):349-59. doi: 10.1016/s0028-3908(98)00204-4.
Abnormal processing of amyloid precursor protein (APP), in particular the generation of beta-amyloid (Abeta) peptides, has been implicated in the pathogenesis of Alzheimer's disease. This study examined the consequences of deleting the APP gene on hippocampal synaptic plasticity, and upon the biophysical properties of morphologically identified neurones in APP-null mice. The hippocampus of APP-null mice had a characteristic increase in gliosis throughout the CA1 region and a disruption of staining for the dendritic marker MAP2 and the presynaptic marker synaptophysin. The disruption of MAP2 staining was associated with a significant reduction in overall dendritic length and projection depth of biocytin labeled CA1 neurones. In two groups of APP-null mice that were examined at 8-12 months, and 20-24 months of age, there was an impairment in the formation of long-term potentiation (LTP) in the CA1 region compared to isogenic age matched controls. This LTP deficit was not associated with an alteration in the amplitude of EPSPs at low stimulus frequencies (0.033 Hz) or facilitation during a 100 Hz stimulus train, but was associated with a reduction in post-tetanic potentiation. Paired-pulse depression of GABA-mediated inhibitory post-synaptic currents was also attenuated in APP-null mice. These data demonstrate that the impaired synaptic plasticity in APP deficient mice is associated with abnormal neuronal morphology and synaptic function within the hippocampus.
淀粉样前体蛋白（APP）的异常加工，尤其是β-淀粉样蛋白（Aβ）肽的产生，与阿尔茨海默病的发病机制有关。本研究检测了APP基因缺失对海马突触可塑性以及对APP基因敲除小鼠中形态学鉴定神经元生物物理特性的影响。APP基因敲除小鼠的海马在整个CA1区域有特征性的胶质增生增加，并且树突标记物MAP2和突触前标记物突触素的染色出现破坏。MAP2染色的破坏与生物胞素标记的CA1神经元的总体树突长度和投射深度的显著减少有关。在8至12个月龄和20至24个月龄时检测的两组APP基因敲除小鼠中，与同基因年龄匹配的对照相比，CA1区域的长时程增强（LTP）形成受损。这种LTP缺陷与低刺激频率（0.033Hz）下的兴奋性突触后电位（EPSP）幅度改变或100Hz刺激串期间的易化无关，但与强直后增强的减少有关。APP基因敲除小鼠中GABA介导的抑制性突触后电流的双脉冲抑制也减弱。这些数据表明，APP缺陷小鼠中受损的突触可塑性与海马内异常的神经元形态和突触功能有关。
