Department of Neuroscience and Farber Institute for Neurosciences, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.
J Neurosci. 2013 Apr 17;33(16):7020-6. doi: 10.1523/JNEUROSCI.2325-12.2013.
BACE1 is the rate-limiting enzyme that cleaves amyloid precursor protein (APP) to produce the amyloid β peptides that accumulate in Alzheimer's disease (AD). BACE1, which is elevated in AD patients and APP transgenic mice, also cleaves the β2-subunit of voltage-gated sodium channels (Navβ2). Although increased BACE1 levels are associated with Navβ2 cleavage in AD patients, whether Navβ2 cleavage occurs in APP mice had not yet been examined. Such a finding would be of interest because of its potential impact on neuronal activity: previous studies demonstrated that BACE1-overexpressing mice exhibit excessive cleavage of Navβ2 and reduced sodium current density, but the phenotype associated with loss of function mutations in either Navβ-subunits or pore-forming α-subunits is epilepsy. Because mounting evidence suggests that epileptiform activity may play an important role in the development of AD-related cognitive deficits, we examined whether enhanced cleavage of Navβ2 occurs in APP transgenic mice, and whether it is associated with aberrant neuronal activity and cognitive deficits. We found increased levels of BACE1 expression and Navβ2 cleavage fragments in cortical lysates from APP transgenic mice, as well as associated alterations in Nav1.1α expression and localization. Both pyramidal neurons and inhibitory interneurons exhibited evidence of increased Navβ2 cleavage. Moreover, the magnitude of alterations in sodium channel subunits was associated with aberrant EEG activity and impairments in the Morris water maze. Together, these results suggest that altered processing of voltage-gated sodium channels may contribute to aberrant neuronal activity and cognitive deficits in AD.
BACE1 是一种切割淀粉样前体蛋白（APP）的限速酶，可产生在阿尔茨海默病（AD）中积累的淀粉样 β 肽。在 AD 患者和 APP 转基因小鼠中，BACE1 水平升高，也可切割电压门控钠通道（Navβ2）的 β2 亚基。虽然 AD 患者中 BACE1 水平升高与 Navβ2 切割有关，但 APP 小鼠中是否发生 Navβ2 切割尚未得到检验。这一发现很有意义，因为它可能对神经元活动产生影响：先前的研究表明，BACE1 过表达小鼠表现出 Navβ2 的过度切割和钠电流密度降低，但 Navβ 亚基或孔形成 α 亚基功能丧失突变相关的表型是癫痫。因为越来越多的证据表明癫痫样活动可能在 AD 相关认知缺陷的发展中起重要作用，我们研究了 APP 转基因小鼠中是否存在 Navβ2 切割增强，以及它是否与异常神经元活动和认知缺陷有关。我们发现 APP 转基因小鼠皮质裂解物中 BACE1 表达水平升高和 Navβ2 切割片段增加，以及 Nav1.1α 表达和定位的改变。锥体细胞和抑制性中间神经元都表现出 Navβ2 切割增加的证据。此外，钠通道亚基的改变幅度与异常 EEG 活动和 Morris 水迷宫中的损伤有关。总之，这些结果表明，电压门控钠通道的异常加工可能导致 AD 中的异常神经元活动和认知缺陷。
