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The normal function of BACE1 remains largely unknown, and a better understanding of its function(s) will be of value in anticipating potential adverse effects of BACE1 inhibition as a therapeutic strategy. This is highlighted by the finding that Aβ generation, amyloid pathology, electrophysiological dysfunction, and cognitive deficits characteristic of APP transgenic mice are all abrogated by genetic deletion of BACE1. Because of its role in Aβ production, BACE1 is a promising drug target for AD. The β-secretase has been identified as a transmembrane aspartic protease referred to as BACE1. APP is first cleaved by the β-secretase at the N-terminus of Aβ to produce the membrane-bound C99 fragment, which is further cleaved by γ-secretase to release Aβ. This and other lines of evidence strongly suggest that Aβ plays a central and early role in AD pathogenesis (reviewed in ).Īβ is produced through the endoproteolysis of the amyloid precursor protein (APP) by two proteases, the β- and γ-secretases (reviewed in ). Mutations that cause autosomal dominant familial AD (FAD) all lead to increased production of Aβ, particularly in its 42-amino acid isoform (Aβ 42) (reviewed in ). One promising approach to such a therapy is to inhibit the production of the β-amyloid (Aβ) peptide, which is the primary constituent of amyloid plaques that represent a major histopathological hallmark of AD.
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Disease modifying therapies for AD are greatly needed, but remain elusive. Further, we demonstrate that altered sodium channel expression and axonal localization are insufficient to account for the observed effect, warranting investigation of alternative mechanisms.Īlzheimer's disease (AD) is a common and devastating neurodegenerative disorder involving a decline in memory and other cognitive functions. This finding has implications for the development of safe therapeutic strategies for reducing Aβ levels in Alzheimer's disease. Our data indicate that BACE1 deficiency predisposes mice to spontaneous and pharmacologically-induced seizure activity.
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Finally, examination of the expression and localization of the voltage-gated sodium channel α-subunit Na v1.2 reveals no correlation with BACE1 genotype or any measure of seizure susceptibility. This hyperexcitability phenotype is variable and appears to be manifest in approximately 30% of BACE1 -/- mice. In addition, we find that kainic acid injection induces seizures of greater severity in BACE1 -/- mice relative to BACE1 +/+ littermates, and causes excitotoxic cell death in a subset of BACE1 -/- mice. We find that electroencephalographic recordings reveal epileptiform abnormalities in some BACE1 -/- mice, occasionally including generalized tonic-clonic and absence seizures. Here we report a seizure-susceptibility phenotype that we have identified and characterized in BACE1 -/- mice. Examination of BACE1 -/- mice can provide insight into this function and also help anticipate consequences of BACE1 inhibition. While BACE1 is an attractive therapeutic target, its normal physiological function remains largely unknown. BACE1 is a key enzyme in the generation of the Aβ peptide that plays a central role in the pathogenesis of Alzheimer's disease.