Genetic Suppression of Transgenic APP Rescues Hypersynchronous Network Activity in a Mouse Model of Alzeimer's Disease
Genetic Suppression of Transgenic APP Rescues Hypersynchronous Network Activity in a Mouse Model of Alzeimer's Disease
复制标题
DOI：
10.1523/jneurosci.5171-13.2014
复制
发表时间：
2014-03-12
影响因子：
5.3
通讯作者：
Jankowsky, Joanna L.
中科院分区：
文献类型：
--
作者：
Born, Heather A.;Kim, Ji-Yoen;Jankowsky, Joanna L.
阿尔茨海默病（AD）与癫痫发作的风险升高有关，癫痫发作可能与认知功能障碍有关。支持这种联系，许多AD小鼠模型除了预期的神经病理学和认知缺陷外，还表现出异常的脑电图（EEG）活动。在这里，我们使用了一个可控的转基因系统来研究网络变化是如何发展和维持在一个模型的特点是淀粉样蛋白β（A β）过度生产和进行性淀粉样蛋白病理。从出生起就过度表达淀粉样前体蛋白（APP）的tet off小鼠的EEG记录显示频繁的尖波放电（SWD）。出乎意料的是，我们发现，抑制APP过度表达，直到成年大大推迟癫痫样活动的出现。总之，这些发现表明，青少年APP过度表达改变了皮质发育，有利于同步放电。无论EEG异常出现的年龄，表型依赖于持续的APP过度表达，一旦转基因表达被抑制，数周后就会减弱。异常EEG放电与斑块负荷无关，并且可以在不改变沉积的淀粉样蛋白的情况下熄灭。用γ-分泌酶抑制剂选择性减少A β对SWD的频率没有影响，表明另一个APP片段或全长蛋白可能是维持EEG异常的原因。此外，转基因抑制正常化的比例兴奋抑制神经支配的皮质，而分泌酶抑制没有。我们的研究结果表明，APP过度表达，而不是A β过度生产，是我们的转基因小鼠的脑电图异常的原因，可以独立于病理学进行抢救。
Alzheimer's disease (AD) is associated with an elevated risk for seizures that may be fundamentally connected to cognitive dysfunction. Supporting this link, many mouse models for AD exhibit abnormal electroencephalogram (EEG) activity in addition to the expected neuropathology and cognitive deficits. Here, we used a controllable transgenic system to investigate how network changes develop and are maintained in a model characterized by amyloid beta (A beta) overproduction and progressive amyloid pathology. EEG recordings in tet-off mice overexpressing amyloid precursor protein (APP) from birth display frequent sharp wave discharges (SWDs). Unexpectedly, we found that withholding APP overexpression until adulthood substantially delayed the appearance of epileptiform activity. Together, these findings suggest that juvenile APP overexpression altered cortical development to favor synchronized firing. Regardless of the age at which EEG abnormalities appeared, the phenotype was dependent on continued APP overexpression and abated over several weeks once transgene expression was suppressed. Abnormal EEG discharges were independent of plaque load and could be extinguished without altering deposited amyloid. Selective reduction of A beta with a gamma-secretase inhibitor has no effect on the frequency of SWDs, indicating that another APP fragment or the full-length protein was likely responsible for maintaining EEG abnormalities. Moreover, transgene suppression normalized the ratio of excitatory to inhibitory innervation in the cortex, whereas secretase inhibition did not. Our results suggest that APP overexpression, and not A beta overproduction, is responsible for EEG abnormalities in our transgenic mice and can be rescued independently of pathology.