Abstract
Caspase-6 (Casp6) is implicated in Alzheimer disease (AD) cognitive impairment and pathology. Hippocampal atrophy is associated with cognitive impairment in AD. Here, a rare functional exonic missense CASP6 single nucleotide polymorphism (SNP), causing the substitution of asparagine with threonine at amino acid 73 in Casp6 (Casp6N73T), was associated with hippocampal subfield CA1 volume preservation. Compared to wild type Casp6 (Casp6WT), recombinant Casp6N73T altered Casp6 proteolysis of natural substrates Lamin A/C and α-Tubulin, but did not alter cleavage of the Ac-VEID-AFC Casp6 peptide substrate. Casp6N73T-transfected HEK293T cells showed elevated Casp6 mRNA levels similar to Casp6WT-transfected cells, but, in contrast to Casp6WT, did not accumulate active Casp6 subunits nor show increased Casp6 enzymatic activity. Electrophysiological and morphological assessments showed that Casp6N73T recombinant protein caused less neurofunctional damage and neurodegeneration in hippocampal CA1 pyramidal neurons than Casp6WT. Lastly, CASP6 mRNA levels were increased in several AD brain regions confirming the implication of Casp6 in AD. These studies suggest that the rare Casp6N73T variant may protect against hippocampal atrophy due to its altered catalysis of natural protein substrates and intracellular instability thus leading to less Casp6-mediated damage to neuronal structure and function.
Highlights
Caspase-6 (Casp6) is implicated in Alzheimer disease (AD) cognitive impairment and pathology
Our study demonstrates that a rare human Caspase‐6 gene (CASP6) variant encoding Casp6N73T, genetically associated with preserved hippocampal Cornu Ammonis 1 (CA1) volume in an AD cohort, exhibits altered catalyses on natural protein substrates, lamin A and α-Tubulin
The significant association between Casp6N73T and hippocampal CA1 volume by sequence kernel association test (SKAT-O) provides an advantage in identifying associations between low frequency functional exonic single nucleotide polymorphism (SNP) and pathological features of AD compared to genome-wide association studies (GWAS)[45,51]
Summary
Caspase-6 (Casp6) is implicated in Alzheimer disease (AD) cognitive impairment and pathology. CASP6 mRNA levels were increased in several AD brain regions confirming the implication of Casp[6] in AD These studies suggest that the rare Casp6N73T variant may protect against hippocampal atrophy due to its altered catalysis of natural protein substrates and intracellular instability leading to less Casp6-mediated damage to neuronal structure and function. Overexpression of wild type or mutant forms of amyloid precursor protein (APP) associated with familial AD induces Casp6dependent, but amyloid beta peptide (Aβ) independent, neurodegeneration in human n eurons[16]. This eventually leads to neuronal cell death that is Aβ dependent. Microinjected active Casp[6] causes neuronal degeneration and impairs synaptic transmission in CA1 pyramidal neurons, but not in medium spiny n eurons[22]
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