Research ArticleNeuroscience

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

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Science Signaling  25 Jun 2019:
Vol. 12, Issue 587, eaaw9318
DOI: 10.1126/scisignal.aaw9318

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Halting the onset of amyloid-induced dementia

The appearance of β-amyloid (Aβ) plaques in the brain is strongly correlated with advanced Alzheimer’s disease (AD) and directly implicated in the neuronal degeneration that underlies cognitive decline in patients. Henderson et al. used a transgenic mouse that expresses a genetic cause of inherited (familial) AD and spontaneously develops Aβ plaques and the neurodegeneration seen in patients. Treating these mice with inhibitors of either the kinase ROCK2 or its downstream target LIMK1 before Aβ plaques were detectable prevented the neuronal morphology alterations subsequently caused by Aβ accumulation. Thus, these inhibitors, which are already in preclinical or clinical trials for patients with cancer, may be prophylactic in individuals at high risk for developing AD.

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.

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