摘要：SummaryPreviously, we found that amyloid-beta (Aβ) competitively inhibits the kinesin motor protein KIF11 (Kinesin-5/Eg5), leading to defects in the microtubule network and in neurotransmitter and neurotrophin receptor localization and function. These biochemical and cell biological mechanisms for Aβ-induced neuronal dysfunction may underlie learning and memory defects in Alzheimer’s disease (AD). Here, we show that KIF11 overexpression rescues Aβ-mediated decreases in dendritic spine density in cultured neurons and in long-term potentiation in hippocampal slices. Furthermore,Kif11overexpression from a transgene prevented spatial learning deficits in the 5xFAD mouse model of AD. Finally, increasedKIF11expression in neuritic plaque-positive AD patients’ brains was associated with better cognitive performance and higher expression of synaptic protein mRNAs. Taken together, these mechanistic biochemical, cell biological, electrophysiological, animal model, and human data identify KIF11 as a key target of Aβ-mediated toxicity in AD, which damages synaptic structures and functions critical for learning and memory in AD.Graphical abstractDisplay OmittedHighlights•Cognitive deficits in 5xFAD mice are prevented byKif11overexpression•Kif11overexpression prevents deficits in long-term potentiation in 5xFAD mice•Aβ-mediated dendritic spine loss is blocked byKif11overexpression•HigherKIF11expression in brain correlates with better cognition in AD patientsPathophysiology; Cellular neuroscience; Cell biology.
