T-type calcium channel enhancer SAK3 improves cognition and inhibits amyloid beta accumulation in AppNL-F knock-in mice

[Speaker] Hisanao Izumi:1
[Co-author] Yasuharu Shinoda:1, Takashi Saito:2, Takaomi Saido:2, Yusaku Nakabeppu:3, Kohji Fukunaga:1
1:Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Japan, 2:Laboratory for Proteolytic Neuroscience, Brain Science Institute, RIKEN, Japan, 3:Division of Neurofunctional Genomics, Department of Immunobiology and Neuroscience, Medical Institute of Bioregulation, Japan

[Background and Objectives] Alzheimer's disease (AD) is a progressive neurodegenerative and the most common disease of elderly dementia in the world. Acetylcholinesterase inhibitors such as donepezil and rivastigmine are the most useful drug for AD, but they are only used as symptomatic treatment and not disease-modifying drugs. Recently, we developed an disease-modifying drug, SAK3 which stimulates T-type calcium channels. We here addressed the proof-of-concept (POC) whether SAK3 chronic treatment can improve cognition and amyloid beta accumulation using AppNL-F knock-in mice.
[Methods] App knock-in mice were chronically and orally administered with SAK3 for 3 months. (i) Behavioral analyses were carried out to assess cognitive functions. (ii) Amyloid beta levels in the brain were quantified by amyloid beta ELISA kit. (iii) Amyloid beta depositions were assessed by staining with 6E10 and Thioflavin-S. (iv) Microarray and RT-PCR analyses were conducted to elucidate the mechanism underlying the inhibition of amyloid beta deposition by SAK3 treatment. (v) A pharmacokinetics using SAK3-d10 was examined by UPLC-MS/MS systems.
[Results] SAK3 chronic administration improved cognitive deficits and inhibited amyloid beta production and deposition in AppNL-F knock-in mice. Whole RNA analysis revealed that mRNA levels of enzymes involved in production and clearance of amyloid beta are not changed by SAK3 administration. Interestingly, mRNA and protein levels of SGK1 were changed SAK3 administration. Finally, Pharmacokinetic analyses confirmed that SAK3-d10 is quickly absorbed and disappeared from body within 12 hrs. In the brain, SAK3-d10 level was reached at concentrations enough to stimulate T-type calcium channels.
[Conclusions] We defined the POC of pharmacokinetics and pharmacodynamics of SAK3 as AD therapeutics using AppNL-F KI mice. These results strongly suggest that SAK3 is a novel disease-modifying AD therapeutics.

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