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

Abstract

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

ΔFosB Regulates Gene Expression and Cognitive Dysfunction in a Mouse Model of Alzheimer’s Disease

“…All of these lines of mice express human APP with mutations linked to autosomal dominant AD, produce high levels of Aβ (Chin, 2011), and exhibit epileptiform activity (Chin and Scharfman, 2013; Corbett et al, 2013; Kam et al, 2016; Minkeviciene et al, 2009; Palop et al, 2007). Notably, similarly aged I5A mice, which overexpress wild-type human APP and do not produce high levels of Aβ (Mucke et al, 2000), do not exhibit increased ΔFosB (Figure 1L, Figure S1G).…”

Blood Genome-Wide Transcriptional Profiles Reflect Broad Molecular Impairments and Strong Blood-Brain Links in Alzheimer's Disease

“…It is therefore possible that ion channel dysregulation in the blood may correlate with the loss of neurological function and complex tissue damage in AD. Previous studies have indicated that the impairment of Na + and Ca ++ signaling may contribute to neuronal dysfunction and cognitive deficits in AD [66, 67]. Further investigation is needed to determine the association between ion channel dysregulation and AD neuropathology.…”

Ion channel regulation by β-secretase BACE1 – enzymatic and non-enzymatic effects beyond Alzheimer's disease

“…59 They observed increased BACE1 levels and b2 cleavage, accompanied by increased Na v 1.1 total, but decreased surface expression in cortical pyramidal cells and interneurons, accompanied by aberrant EEG activity. Verret et al found reduced total Na v 1.1 levels in another strain of APP-over-expressing mice and the parietal cortex of AD patients, which was in line with reduced functional Na v 1.1 in the previous studies.…”