SAK3 Administration Improves Spine Abnormalities and Cognitive Deficits in AppNL-G-F/NL-G-F Knock-in Mice by Increasing Proteasome Activity through CaMKII/Rpt6 Signaling.

Abstract

Alzheimer's disease (AD) is the most common form of dementia and is characterized by neuropathological hallmarks consisting of accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFT). Recently, we have identified a new AD therapeutic candidate, ethyl-8'-methyl-2',4-dioxo-2-(piperidin-1-yl)-2'H-spiro[cyclopentane-1,3'-imidazo [1,2-a] pyridin]-2-ene-3-carboxylate (SAK3), which ameliorates the AD-like pathology in AppNL-F/NL-F knock-in mice. However, the detailed mechanism underlying the therapeutic effects of SAK3 remains unclear. In this study, we found that SAK3 administration improved the reduced proteasome activity through the activation of CaMKII/Rpt6 signaling in AppNL-F/NL-F knock-in (NL-G-F) mice. Moreover, spine abnormalities observed in NL-G-F mice were significantly reversed by SAK3 administration. Along with this, cognitive impairments found in NL-G-F mice were markedly ameliorated by SAK3. In summary, our data suggest that SAK3 administration increases the activity of the proteasome via activation of the CaMKII/Rpt6 signaling pathway, contributing to improvements in spine abnormalities and cognitive deficits in NL-G-F mice. Overall, our findings suggest that SAK3 might be a new attractive drug candidate, representing a new mechanism for the treatment of AD pathology.

• Authors: Hisanao Izumi, Ichiro Kawahata, Yasuharu Shinoda, Fred J Helmstetter, Kohji Fukunaga
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 11 (May 28 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32481611 (Publication Type: Journal Article)

Chemical References

• APP protein, mouse
• Amyloid beta-Peptides
• Amyloid beta-Protein Precursor
• Imidazoles
• Psmc5 protein, mouse
• SAK3 compound
• Spiro Compounds
• Calcium-Calmodulin-Dependent Protein Kinase Type 2
• Proteasome Endopeptidase Complex
• ATPases Associated with Diverse Cellular Activities

Topics

• ATPases Associated with Diverse Cellular Activities (genetics)
• Alzheimer Disease (metabolism)
• Amyloid beta-Peptides (metabolism)
• Amyloid beta-Protein Precursor (genetics)
• Animals
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (genetics)
• Cognitive Dysfunction (drug therapy, metabolism)
• Dendritic Spines (metabolism)
• Female
• Gene Knock-In Techniques
• Imidazoles (pharmacology)
• Liver (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Neurofibrillary Tangles (metabolism)
• Phosphorylation
• Plaque, Amyloid (metabolism)
• Proteasome Endopeptidase Complex (genetics, metabolism)
• Signal Transduction
• Spine (pathology)
• Spiro Compounds (pharmacology)