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Puromycin Sensitive Aminopeptidase (PSA/NPEPPS) has neuroprotective effect in the mouse model of TAU induced neurodegeneration
Author(s) -
Karsten Stanislav L.,
Parfenova Liubov,
Lau Kimbley,
Vi Nancy,
Hui Maria,
Gray Michelle,
Yang X. William,
Hui KoonSea,
Kudo Lili C.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.lb413
Subject(s) - neuroprotection , neurodegeneration , genetically modified mouse , in vivo , transgene , western blot , endocrinology , biology , pharmacology , medicine , neuroscience , disease , biochemistry , microbiology and biotechnology , gene
Previously we identified PSA as a novel modifier of TAU‐induced neurodegeneration with effects via direct proteolysis of TAU protein. To investigate PSA's effects in the mammalian system in vivo, we generated PSA transgenic mice using BAC mediated technology. PSA mice reveal no gross anatomical or behavioral abnormalities. PSA expression and activity were elevated in the brain and other organs of hemizygous PSA mice 2 to 3 fold compared to controls. PSA mice have no significant changes in enkephalin turnover/degradation, indicating PSA is not a primary enkephalinase. To test PSA's neuroprotective ability in vivo, we crossed our PSA mice with TAUP301L transgenic mice. PSA/TAUP301L mice develop paralysis up to 1.5 months later than TAUP301L mice and show improved motor neuron counts. Immunohistochemistry showed reduced levels of hyperphosphorylated TAU in multiple brain regions of PSA/TAUP301L mice. Western blot analysis of adult and aged PSA/TAUP301L mice exhibit complete elimination of human mutated TAU. Our data confirm that elevating PSA activity in vivo blocks accumulation of soluble toxic TAU protein and may slow down the disease progression, making it a feasible therapeutic approach to treat tauopathies such as Alzheimer's disease. This work was supported by UCLA Alzheimer's Disease Research Center (SLK), CurePSP (SLK), Alzheimer's Association (SLK, LCK) and NARSAD (SLK).