Roles of CCNY in the amyloid pathology of Alzheimer’s disease

Abstract

AbstractBackgroundAlzheimer’s disease (AD), the most common form of dementia, has three major pathological features; Aβ plaque, tau tangles, and neuroinflammation. Many studies have focused on developing treatments for AD; however, many clinical trials have failed. It recently has been discussed that depletion of Cyclin Y(CCNY) ameliorates impaired memory function by inhibiting memory plasticity by AMPA receptor. However, very little is known about the molecular mechanisms between CCNY and AD progression. Also, it remains controversial whether CCNY accelerates amyloid pathology or halts it.MethodWe crossed CCNY KO mice with 5xFAD, making 4 groups for the project; WT, CCNY KO, 5xFAD, 5xFAD;CCNY KO. Behavioural tests were conducted at the age of 10 months with Morris Water Maze(MWM) and Elevated Plus Maze(EPM). Brain tissue was collected using perfusion and then analyzed with ELISA, Immunohistochemistry (IHC), Thio‐flavin S(Thio‐S) staining, and RNA sequencing.ResultIn MWM and EPM tests, 5xFAD;CCNY−/− mice showed worse cognition level compared to 5xFAD mice. Analysis of Aβ1‐42 using ELISA illustrated the increased level of Aβ1‐42 in both cortex and hippocampus of 5xFAD;CCNY−/− mice. Aβ plaque level resulted from IHC sustainably upregulated in 5xFAD;CCNY−/− mice. Deficiency of CCNY described bigger size of senile plaques through Thio‐S staining in 5xFAD mice in contrast with 5xFAD mice. Activation of microglia was upregulated in 5xFAD;CCNY−/− mice confirmed via IHC.ConclusionIn this research, we investigated the role of CCNY in Aβ processing and neuroinflammation. This study demonstrates the association between CCNY and AD, illustrating CCNY as a regulator in the pathogenesis of Aβ plaque and as a candidate for AD therapy.