Increased Expression of Kif11/Kinesin‐5 mRNA Offsets Cognitive Deficits In An Alzheimer’s Mouse Model, Blocks Aβ‐Mediated Decreases in Long‐Term Potentiation and Spine Density, and is Associated With Better Cognitive Performance in Alzheimer’s Patients

Abstract

AbstractBackgroundInteractions between the Aβ with intra‐ and extra‐cellular molecules disrupt neuronal structures and functions, leading to cognitive dysfunction in Alzheimer’s disease (AD). We previously have shown that Aβ competitively inhibits the microtubule motor protein KIF11 (Kinesin‐5/Eg5), which regulates microtubule dynamics, cellular trafficking, neuronal migration, and neuronal structures important for learning and memory. In vitro cell culture and ex vivo electrophysiology experiments later revealed that the inhibition of KIF11 by Aβ underlies multiple phenotypes associated with AD, including decreases in LTP, breakdown of the microtubule network, and deficits in neurotransmitter receptor localization and function. Here we aimed to determine whether increased Kif11 expression overrides phenotypes associated with AD.MethodsKif11 overexpressing mice were crossed with the 5xFAD mouse model of AD to generate 5xFAD mice that overexposes Kif11. Learning and memory of these mice was measured through the performance of 6‐8 month old mice in the radial‐arm water maze and LTP was measured by the fEPSP response to high‐frequency stimulation of the CA1 region in hippocampal slices of our transgenic mice. Primary rat neurons were transiently transfected to express human APP harboring the Swedish mutation (APPswe) with or without Kif11 overexpression to determine whether increased Kif11 expression affects Aβ‐mediated decreases in dendritic spine, We then evaluated cognitive function in amyloid positive individuals in the ROS/MAP study with their KIF11 mRNA expression in 4 brain regions, the DLPFC (N = 939), PCC (N = 527), and the CN (N = 715).ResultsKIF11 overexpression overrides Aβ toxicity and rescues Aβ‐mediated decreases in LTP in hippocampal slices and dendritic spine density in cultured neurons. Furthermore, we found that spatial and working memory deficits were prevented in a 5xFAD Alzheimer’s mouse model that overexpresses Kif11. Analyses of RNAseq data from human participants in the Religious Order Study and Memory and Aging (ROS/MAP) revealed that higher KIF11 expression in AD patients correlated with better cognitive performance.ConclusionKIF11 is essential for maintaining synaptic structures and functions critical for learning and memory in AD, and preventing or overriding the inhibitory interaction of Aβ with Kif11 could be a promising therapeutic target for multiple AD phenotypes.