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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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  • Usage
    309
    • Abstract Views
      298
    • Downloads
      11

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.

Bibliographic Details

Esteban Lucero; Ronald Freund; Alexandra Smith; Noah Johnson; Breanna Dooling; Emily Sullivan; Olga Prikhodko; Md. Mahiuddin Ahmed; David A. Bennett; Timothy Hohman; Mark Dell'Acqua; Heidi Chial; Huntington Potter

Elsevier BV

Alzheimer's disease (AD); 5xFAD; Kif11; Kinesin-5; Eg5; microtubules; Alzheimer's mouse model; neuronal structures; motor protein; learning and memory; amyloid-beta (A)

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