Increased KIF11/kinesin-5 expression offsets Alzheimer Aβ-mediated toxicity and cognitive dysfunction

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

iScience (Nov 2022)

Increased KIF11/kinesin-5 expression offsets Alzheimer Aβ-mediated toxicity and cognitive dysfunction

Esteban M. Lucero,
Ronald K. Freund,
Alexandra Smith,
Noah R. Johnson,
Breanna Dooling,
Emily Sullivan,
Olga Prikhodko,
Md. Mahiuddin Ahmed,
David A. Bennett,
Timothy J. Hohman,
Mark L. Dell’Acqua,
Heidi J. Chial,
Huntington Potter

Affiliations

Esteban M. Lucero: Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Program for Human Medical Genetics and Genomics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Ronald K. Freund: University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Alexandra Smith: Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
Noah R. Johnson: Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Breanna Dooling: Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Program for Human Medical Genetics and Genomics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Emily Sullivan: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Olga Prikhodko: Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Md. Mahiuddin Ahmed: Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
David A. Bennett: Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA; Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA
Timothy J. Hohman: Vanderbilt Memory and Alzheimer’s Center, Vanderbilt University Medical Center, Nashville, TN, USA; Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA
Mark L. Dell’Acqua: University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Heidi J. Chial: Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA
Huntington Potter: Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; University of Colorado Alzheimer’s and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA; Corresponding author

Journal volume & issue: Vol. 25, no. 11
p. 105288

Abstract

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Summary: 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. 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, 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’ 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.

Published in iScience

ISSN: 2589-0042 (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Science
Website: http://www.cell.com/iscience/home

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