Molecular And Functional Characterization Of Kv2.1 Cleavaged By BACE1:Implication In Alzheimer’s Disease

Alzheimer’s disease (AD) is the most common neurodegenerative disease.The pathological features of AD are:senile plaques、neurofibrillary tangles and loss of neurons. Its etiology is associated withβ-amyloid(AP) abnormal deposition. The major component of senile plaques is Aβ. Aβ peptide is generated following the sequential cleavage of amyloid precursor protein (APP) by β-and y-secretase in the amyloidogenic pathway.At present, β-site APP cleaving enzyme 1 (BACE1) and BACE2 are considered to be two main β-secretases. Although BACE1 as a kind of transmembrane aspartic protease expressed in all tissues, but its mRNA expression in the pancreas is the highest. The expression in the brain is very high too. Gene expression of BACE1 is regulated strictly in transcription. A large number of recent studies have found that the BACE1 knockout mice show abnormal myelin formation and abnormal behavior performance, which suggested that the protease has important function in nervous system development process.Kv2.1 is located in neuronal cell bodies and proximal dendrites in the form of high density cluster, influencing the excitability of neurons and apoptosis. There are four alpha subunits in Kv2.1. Each peptide has six transmembrane regions and extensive N- and C-terminal cytoplasmic domains. It has six transmembrane segments S1-S6 arranged in modular voltage-sensing (S1-S4) and pore-forming (S5-S6) domains. Previous studies have shown that Kv2.1 channel plays an important role in the process of neurodegeneration induced by oxidative stress. Recent studies have found that Kv2.1 is sensitive to oxidative stress. Oxidation conditions can induce the formation of internal disulfide bond bridge, making Kv2.1 oligomerization and inactivation. Kv2.1 in older rat brain is oxidated obviously, which is more serious in the brains of Alzheimer’s disease patients.Kv2.1 can also control cell apoptosis.Our study suggested that Kv2.1 can be cleaved by BACE1. There are three cleavage sites in Kv2.1,located in KV2.1-489-508, KV2.1-540-560 and KV2.1-700-720.