Overexpression of LIMK1 in hippocampal excitatory neurons improves synaptic plasticity and social recognition memory in APP/PS1 mice

Haiwang Zhang,An Liu,Youssif Ben Zablah,Yanghong Meng,Zhengping Jia,Haorui Zhang,Dongju Lee,Xingde Liu,Yiming Wang,Changxi Zhou

doi:10.1186/s13041-021-00833-3

Abstract

Accumulating evidence indicates that the actin regulator cofilin is overactivated in Alzheimer’s Disease (AD), but whether this abnormality contributes to synaptic and cognitive impairments in AD is unclear. In addition, the brain region and cell types involved remain unknown. In this study, we specifically manipulate LIMK1, the key protein kinase that phosphorylates and inactivates cofilin, in the hippocampus of APP/PS1 transgenic mice. Using local injections of the AAV virus containing LIMK1 under the control of the CaMKIIα promoter, we show that expression of LIMK1 in hippocampal excitatory neurons increases cofilin phosphorylation (i.e., decreases cofilin activity), rescues impairments in long-term potentiation, and improves social memory in APP/PS1 mice. Our results suggest that deficits in LIMK1/cofilin signaling in the hippocampal excitatory neurons contribute to AD pathology and that manipulations of LIMK1/cofilin activity provide a potential therapeutic strategy to treat AD.

Highlights

Alzheimer’s Disease (AD) is the leading cause of dementia, but no effective treatment or cure is currently available
Impaired social memory in amyloid precursor protein (APP)/PS1 mice We focused on social behavior and memory in 3-month old mice because this aspect is relatively less studied compared to other cognitive processes in APP/PS1 transgenic mice
In the three-chamber social interaction test (Fig. 1A) that consisted of three stages, both APP/PS1 and wild-type (WT) littermates spent more time interacting with the stranger 1 (S1) than the empty cage, suggesting that sociability was not altered in APP/PS1 mice (Fig. 1B)

Summary

Introduction

Alzheimer’s Disease (AD) is the leading cause of dementia, but no effective treatment or cure is currently available. Aβ molecules are released to the extracellular space and can aggregate to form soluble oligomers (AβO) or further accumulate into insoluble plaques [1,2,3] How these peptides lead to neuronal degeneration and memory loss remains unclear; LIM domain kinase 1 (LIMK1) is a key signaling molecule critical for actin regulation in the brain. Increased phosphorylated cofilin (i.e., decreased cofilin activity) has been found to be associated with AD models under some circumstances [25, 29,30,31,32,33] These results indicate complex effects of AD pathology on LIMK1/cofilin signaling, and whether and how LIMK1/cofilin contributes to AD pathogenesis remains unclear

Methods

Results

Conclusion