Sodium Channel Cleavage Is Associated with Aberrant Neuronal Activity and Cognitive Deficits in a Mouse Model of Alzheimer's Disease

摘要: BACE1 is the rate-limiting enzyme that cleaves amyloid precursor protein (APP) to produce β peptides accumulate in Alzheimer's disease (AD). BACE1, which elevated AD patients and APP transgenic mice, also β2-subunit of voltage-gated sodium channels (Navβ2). Although increased levels are associated with Navβ2 cleavage patients, whether occurs mice had not yet been examined. Such a finding would be interest because its potential impact on neuronal activity: previous studies demonstrated BACE1-overexpressing exhibit excessive reduced current density, but phenotype loss function mutations either Navβ-subunits or pore-forming α-subunits epilepsy. Because mounting evidence suggests epileptiform activity may play an important role development AD-related cognitive deficits, we examined enhanced it aberrant deficits. We found expression fragments cortical lysates from as well alterations Nav1.1α localization. Both pyramidal neurons inhibitory interneurons exhibited cleavage. Moreover, magnitude channel subunits was EEG impairments Morris water maze. Together, these results suggest altered processing contribute deficits AD.