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

BACE1 is the rate-limiting enzyme that cleaves amyloid precursor protein (APP) to produce the amyloid beta peptides that accumulate in Alzheimer's disease (AD). BACE1, which is elevated in AD patients and APP transgenic mice, also cleaves the beta 2-subunit of voltage-gated sodium channels (Nav beta 2). Although increased BACE1 levels are associated with Nav beta 2 cleavage inADpatients, whether Nav beta 2 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 Nav beta 2 and reduced sodium current density, but the phenotype associated with loss of function mutations in either Nav beta-subunits or pore-forming alpha-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 Nav beta 2 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 Nav beta 2 cleavage fragments in cortical lysates from APP transgenic mice, as well as associated alterations in Nav1.1 alpha expression and localization. Both pyramidal neurons and inhibitory interneurons exhibited evidence of increased Nav beta 2 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.