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

ABSTRACT: Alzheimer's disease (AD) therapies predominantly focus on ?-amyloid (A?), but A? effects may be maximal before clinical symptoms appear. Downstream of A?, 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. A?42 oligomers can activate ROCKs. Here, using static imaging studies combined with multielectrode array analyses, we found that the ROCK2-LIMK1 pathway mediated A?42-induced spine degeneration and neuronal hyperexcitability. Live-cell microscopy revealed that pharmacologic inhibition of LIMK1 rendered dendritic spines resilient to A?42 oligomers. Treatment of hAPP mice with a LIMK1 inhibitor rescued A?-induced hippocampal spine loss and morphologic aberrations. Our data suggest that therapeutically targeting LIMK1 may provide dendritic spine resilience to A? and therefore may benefit cognitively normal patients that are at high risk for developing dementia.

SUBMITTER: Henderson BW

PROVIDER: S-EPMC7088434 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Henderson Benjamin W BW Greathouse Kelsey M KM Ramdas Raksha R Walker Courtney K CK Rao Tejeshwar C TC Bach Svitlana V SV Curtis Kendall A KA Day Jeremy J JJ Mattheyses Alexa L AL Herskowitz Jeremy H JH

Science signaling 20190625 587

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 t ...[more]

PMID: 31239325

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Project description:BackgroundAlzheimer's disease (AD) is the most common neurodegenerative disease worldwide but has no effective treatment. Amyloid beta (Aβ) protein, a primary risk factor for AD, accumulates and aggregates in the brain of patients with AD. Paired immunoglobulin-like receptor B (PirB) has been identified as a receptor of Aβ and Aβ-PirB molecular interactions that cause synapse elimination and synaptic dysfunction. PirB deletion has been shown to suppress Aβ-induced synaptic dysfunction and behavioral deficits in AD model mice, implying that PirB mediates Aβ-induced AD pathology. Therefore, inhibiting the Aβ-PirB molecular interaction could be a successful approach for combating AD pathology. We previously showed that lateral olfactory tract usher substance (LOTUS) is an endogenous antagonist of type1 Nogo receptor and PirB and that LOTUS overexpression promotes neuronal regeneration following damage to the central nervous system, including spinal cord injury and ischemic stroke. Therefore, in this study, we investigated whether LOTUS inhibits Aβ-PirB interaction and Aβ-induced dendritic spine elimination.MethodsThe inhibitory role of LOTUS against Aβ-PirB (or leukocyte immunoglobulin-like receptor subfamily B member 2: LilrB2) binding was assessed using a ligand-receptor binding assay in Cos7 cells overexpressing PirB and/or LOTUS. We assessed whether LOTUS inhibits Aβ-induced intracellular alterations and synaptotoxicity using immunoblots and spine imaging in a primary cultured hippocampal neuron.ResultsWe found that LOTUS inhibits the binding of Aβ to PirB overexpressed in Cos7 cells. In addition, we found that Aβ-induced dephosphorylation of cofilin and Aβ-induced decrease in post-synaptic density-95 expression were suppressed in cultured hippocampal neurons from LOTUS-overexpressing transgenic (LOTUS-tg) mice compared with that in wild-type mice. Moreover, primary cultured hippocampal neurons from LOTUS-tg mice improved the Aβ-induced decrease in dendritic spine density. Finally, we studied whether human LOTUS protein inhibits Aβ binding to LilrB2, a human homolog of PirB, and found that human LOTUS inhibited the binding of Aβ to LilrB2 in a similar manner.ConclusionsThis study implied that LOTUS improved Aβ-induced synapse elimination by suppressing Aβ-PirB interaction in rodents and inhibited Aβ-LilrB2 interaction in humans. Our findings revealed that LOTUS may be a promising therapeutic agent in counteracting Aβ-induced AD pathologies.

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

Publications

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

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