Increased Expression of KIF11/Kinesin5 Offsets Alzheimer Aβ-Mediated Toxicity and Cognitive Dysfunction in Cell Culture, Mice, and Humans
SSRN Electronic Journal
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Article Description
Previously, 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. This discovery revealed biochemical and cell biological mechanisms for the Aβ-induced neuronal dysfunction that underlies the 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 LTP in hippocampal slices. Furthermore, Kif11 overexpression from a transgene prevented spatial learning deficits in the 5xFAD mouse model of AD. Finally, increased KIF11 expression in neuritic plaque-positive AD patients was found to correlate with better cognitive performance. Taken together, these mechanistic biochemical, cell biological, electrophysiological, animal model, and human data identify KIF11 as a key target of Aβ-mediated toxicity required to maintain synaptic structures and functions critical for learning and memory in AD.
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