Premium
O2‐03–03: Depletion of GGA3 regulates BACE in vivo
Author(s) -
Tesco Giuseppina,
Cameron Andrew N.,
Kang Eugene L.,
Tanzi Rudolph E.,
Whalen Michael J.
Publication year - 2008
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2008.05.324
Subject(s) - downregulation and upregulation , in vivo , ischemia , chemistry , signal transducing adaptor protein , pharmacology , microbiology and biotechnology , medicine , biochemistry , signal transduction , biology , gene
has been shown to degrade A . Therefore, NEP2 may be an important A degrading enzyme. Methods: Knockout mice deficient for NEP2 and NEP were analyzed in this study. Specific ELISA for A was used for quantification in vitro and in vivo. Immunoblot and flow cytometry utilizing specific antibodies were used for molecular characterization of NEP2. Results: We have investigated the role of NEP2 in A degradation in vivo. Aged mice deficient for the NEP2 gene showed a 3 fold increase in A 42 levels compared to age and strain matched controls. Furthermore, knockout mice lacking NEP, showed a gene dose dependent increase in A 42 levels inversely correlated with NEP2 gene copy number. Only mild effects were seen on A 40 levels. We have also characterized the human homolog of NEP2. hNEP2 was shown to mediate the degradation of cell produced A 40 and A 42, however, not all splice forms were active. The active variant of NEP2 was shown to be a type-II integral membrane protein similar to NEP. It was also found to be sensitive to thiorphan and phosphoramidon. Finally, NEP2 expression was detected in human brain tissue by RT-PCR. Conclusions: These findings suggest NEP2 is required for maintenance of normal A levels in the brain.