Abstract
To understand the molecular processes that link Aβ amyloidosis, tauopathy and neurodegeneration, we screened for tau-interacting proteins by immunoprecipitation/LC-MS. We identified the carboxy-terminal PDZ ligand of nNOS (CAPON) as a novel tau-binding protein. CAPON is an adaptor protein of neuronal nitric oxide synthase (nNOS), and activated by the N-methyl-D-aspartate receptor. We observed accumulation of CAPON in the hippocampal pyramidal cell layer in the AppNL-G-F -knock-in (KI) brain. To investigate the effect of CAPON accumulation on Alzheimer’s disease (AD) pathogenesis, CAPON was overexpressed in the brain of AppNL-G-F mice crossbred with MAPT (human tau)-KI mice. This produced significant hippocampal atrophy and caspase3-dependent neuronal cell death in the CAPON-expressing hippocampus, suggesting that CAPON accumulation increases neurodegeneration. CAPON expression also induced significantly higher levels of phosphorylated, oligomerized and insoluble tau. In contrast, CAPON deficiency ameliorated the AD-related pathological phenotypes in tauopathy model. These findings suggest that CAPON could be a druggable AD target.
Highlights
We previously developed two lines of novel Alzheimer’s disease (AD) model mice based on an App knock-in (KI) strategy[5]
Cross-breeding of MAPT KI with AppNL-G-F KI did not alter amyloid pathology, neuroinflammation, and neuronal cell death of AppNL-G-F KI (Fig. 1d, e). These findings indicate that humanization of the Mapt gene does not affect neurodegenerative processes
In this study, we have demonstrated that Aβ pathology leads to the accumulation of carboxy-terminal PDZ ligand of neuronal nitric oxide synthase (nNOS) (CAPON) protein, and that the increase in CAPON induces tau pathology and neuronal cell death
Summary
We previously developed two lines of novel AD model mice based on an App (amyloid precursor protein) knock-in (KI) strategy[5]. The second model (AppNL-G-F/NL-G-F; AppNL-G-F) carries an additional mutation (E639G: Arctic mutation), and exhibits aggressive pathology[5,6] Both lines, which produce humanized Aβ without overexpressing APP, show pronounced Aβ amyloidosis, gliosis, and memory deficits[5,7]. We thought that the double-KI mice generated by cross-breeding App KI and hTau-KI mice might show greater AD pathology than the single App-KI mice due to tau humanization, we noted no overt pathological changes in the former mice. These results suggested the presence of mechanisms/factors in addition to Aβ amyloidosis that induce tauopathy and neurodegeneration. The methods used to generate the tau interactome were validated by identification of the tubulin beta-4A chain as one of the tau-binding proteins
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
