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P2‐531: A novel glycogen synthase kinase‐3 inhibitor 2‐methyl‐5‐(3‐{4‐[(s)‐methylsulfinyl]phenyl}‐1‐benzofuran‐5‐yl)‐1,3,4‐oxadiazole (mmbo) decreased tau phosphorylation and ameliorated cognitive deficits in a transgenic model of Alzheimer's disease
Author(s) -
Onishi Tomohiro,
Iwashita Hiroki,
Uno Yumiko,
Kunitomo Jun,
Saitoh Morihisa,
Kimura Eiji,
Fujita Hisashi,
Uchiyama Noriko,
Kori Masakuni,
Takizawa Masayuki
Publication year - 2011
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.2011.05.1400
Subject(s) - gsk 3 , glycogen synthase , phosphorylation , genetically modified mouse , senile plaques , gsk3b , hippocampus , chemistry , in vivo , kinase , tau protein , transgene , neuroscience , pharmacology , alzheimer's disease , medicine , endocrinology , biology , biochemistry , disease , microbiology and biotechnology , gene
potential epitope specificity and safety of this promising therapeutic effect, we are examining several tau epitopes. Here we assessed the efficacy of using a pseudo-phosphorylated tau immunogen. Methods: Homozygous JNPL3 mice were immunized with Tau379-408[ESer396, E-Ser404] in alum adjuvant (n 1⁄4 13) or with adjuvant only (n 1⁄4 7), starting at 2 months. Mice were tested on various sensorimotor tasks (rotarod, traverse beam, locomotor activity and grip strength) at 5 and 8 months of age. Antibody titers were determined and at 8 months their brains were processed for tau biochemistry and histology. Results: The vaccine elicited a robust antibody response towards the immunogen, and its phosphorylated and non-phosphorylated analogs. Which is as expected since this region of the tau protein is highly immunogenic. The immunized mice had a 24% reduction in soluble PHF1/total tau ratio on western blots (p 1⁄4 0.04), and a 42% reduction in PHF1 immunostaining in the dentate gyrus (p < 0.03), compared to alum-treated mice. Levels of sarkosyl insoluble human and total tau were highly variable in both groups and not significantly different. Biochemical and histological analyses with other antibodies and of other brain regions is underway. Disappointingly, potential improvements in motor function of the immunized mice could not be assessed since the animals did not develop overt signs of such impairments at the ages tested, in contrast to our previous observation in the same homozygous model (Asuni A. et al., J. Neurosci., 2007). Unfortunately, such changes in phenotype are commonly observed in transgenic mice.Conclusions: These findings indicate that immunological targeting using a pseudo-phosphorylated tau epitope can reduce pathological tau within the brain, further supporting the feasibility of tau immunotherapy.