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Sci Signal. 2019 Jun 25;12(587). pii: eaaw9318. doi: 10.1126/scisignal.aaw9318.

Pharmacologic inhibition of LIMK1 provides dendritic spine resilience against β-amyloid.

Author information

1
Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
2
Department of Neurology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
3
Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
4
Department of Neurobiology, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA.
5
Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham School of Medicine, Birmingham, AL 35294, USA. jhersko@uab.edu.

Abstract

Alzheimer's disease (AD) therapies predominantly focus on β-amyloid (Aβ), but Aβ effects may be maximal before clinical symptoms appear. Downstream of Aβ, dendritic spine loss correlates most strongly with cognitive decline in AD. Rho-associated kinases (ROCK1 and ROCK2) regulate the actin cytoskeleton, and ROCK1 and ROCK2 protein abundances are increased in early AD. Here, we found that the increased abundance of ROCK1 in cultured primary rat hippocampal neurons reduced dendritic spine length through a myosin-based pathway, whereas the increased abundance of ROCK2 induced spine loss through the serine and threonine kinase LIMK1. Aβ42 oligomers can activate ROCKs. Here, using static imaging studies combined with multielectrode array analyses, we found that the ROCK2-LIMK1 pathway mediated Aβ42-induced spine degeneration and neuronal hyperexcitability. Live-cell microscopy revealed that pharmacologic inhibition of LIMK1 rendered dendritic spines resilient to Aβ42 oligomers. Treatment of hAPP mice with a LIMK1 inhibitor rescued Aβ-induced hippocampal spine loss and morphologic aberrations. Our data suggest that therapeutically targeting LIMK1 may provide dendritic spine resilience to Aβ and therefore may benefit cognitively normal patients that are at high risk for developing dementia.

PMID:
31239325
DOI:
10.1126/scisignal.aaw9318

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