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

doi:10.1016/j.isci.2022.105288

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

iScience. 2022 Oct 7;25(11):105288. doi: 10.1016/j.isci.2022.105288. eCollection 2022 Nov 18.

Authors

Esteban M Lucero^{1

2

3

4}, Ronald K Freund^{2

5}, Alexandra Smith^{6

7}, Noah R Johnson^{1

2

3}, Breanna Dooling^{1

2

3

4}, Emily Sullivan⁵, Olga Prikhodko⁵, Md Mahiuddin Ahmed^{1

2

3}, David A Bennett^{8

9}, Timothy J Hohman^{6

7}, Mark L Dell'Acqua^{2

3

5}, Heidi J Chial^{1

2

3}, Huntington Potter^{1

2

3}

Affiliations

¹ Department of Neurology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² University of Colorado Alzheimer's and Cognition Center, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
³ Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁴ University of Colorado Program for Human Medical Genetics and Genomics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁵ Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
⁶ Vanderbilt Memory and Alzheimer's Center, Vanderbilt University Medical Center, Nashville, TN, USA.
⁷ Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
⁸ Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, IL, USA.
⁹ Department of Neurological Sciences, Rush University Medical Center, Chicago, IL, USA.

Abstract

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.

Keywords: Cell biology; Cellular neuroscience; Pathophysiology.

Grants and funding

F99 NS115330/NS/NINDS NIH HHS/United States