The Disease-modifying Drug Candidate, SAK3 Improves Cognitive Impairment and Inhibits Amyloid beta Deposition in App Knock-in Mice

Hisanao Izumi, Yasuharu Shinoda, Takashi Saito, Takaomi C. Saido, Keita Sato, Yasushi Yabuki, Yotaro Matsumoto, Yoshitomi Kanemitsu, Yoshihisa Tomioka, Nona Abolhassani, Yusaku Nakabeppu, Kohji Fukunaga

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12 Citations (Scopus)

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common form of elderly dementia in the world. At present, acetylcholine inhibitors, such as donepezil, galantamine and rivastigmine, are used for AD therapy, but the therapeutic efficacy is limited. We recently proposed T-type voltage-gated Ca2+ channels’ (T-VGCCs) enhancer as a new therapeutic candidate for AD. In the current study, we confirmed the pharmacokinetics of SAK3 in the plasma and brain of mice using ultra performance liquid chromatography-tandem mass spectrometry. We also investigated the effects of SAK3 on the major symptoms of AD, such as cognitive dysfunction and amyloid beta (Aβ) accumulation, in AppNL-F knock-in (NL-F) mice, which have been established as an AD model. Chronic SAK3 (0.5 mg/kg/day) oral administration for 3 months from 9 months of age improved cognitive function and inhibited Aβ deposition in 12-month-old NL-F mice. Using microarray and real-time PCR analysis, we discovered serum- and glucocorticoid-induced protein kinase 1 (SGK1) as one of possible genes involved in the inhibition of Aβ deposition and improvement of cognitive function by SAK3. These results support the idea that T-VGCC enhancer, SAK3 could be a novel candidate for disease-modifying therapeutics for AD.

Original languageEnglish
Pages (from-to)87-97
Number of pages11
JournalNeuroscience
Volume377
DOIs
Publication statusPublished - May 1 2018

All Science Journal Classification (ASJC) codes

  • Neuroscience(all)

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    Izumi, H., Shinoda, Y., Saito, T., Saido, T. C., Sato, K., Yabuki, Y., Matsumoto, Y., Kanemitsu, Y., Tomioka, Y., Abolhassani, N., Nakabeppu, Y., & Fukunaga, K. (2018). The Disease-modifying Drug Candidate, SAK3 Improves Cognitive Impairment and Inhibits Amyloid beta Deposition in App Knock-in Mice. Neuroscience, 377, 87-97. https://doi.org/10.1016/j.neuroscience.2018.02.031