Background:Vascular cognitive impairment caused by chronic cerebral hypoperfusion(CCH)has become a hot issue worldwide.Aerobic exercise positively contributes to the preservation or restoration of cognitive abilities;however,the specific mechanism has remained inconclusive.And recent studies found that neurogranin(Ng)is a potential biomarker for cognitive impairment.This study aims to investigate the underlying role of Ng in swimming training to improve cognitive impairment.Methods:To test this hypothesis,the clustered regularly interspaced short palindromic repeats(CRISPR)-associated protein 9(Cas9)system was utilized to construct a strain of Ng conditional knockout(Ng cKO)mice,and bilateral common carotid artery stenosis(BCAS)surgery was performed to prepare the model.In Experiment 1,2-month-old male and female transgenic mice were divided into a control group(wild-type littermate,n=9)and a Ng cKO group(n=9).Then,2-month-old male and female C57BL/6 mice were divided into a sham group(C57BL/6,n=12)and a BCAS group(n=12).In Experiment 2,2-month-old male and female mice were divided into a sham group(wild-type littermate,n=12),BCAS group(n=12),swim group(n=12),BCAS+Ng cKO group(n=12),and swim+Ng cKO group(n=12).Then,7 days after BCAS,mice were given swimming training for 5 weeks(1 week for adaptation and 4 weeks for training,5 days a week,60 min a day).After intervention,laser speckle was used to detect cerebral blood perfusion in the mice,and the T maze and Morris water maze were adopted to test their spatial memory.Furthermore,electrophysiology and Western blotting were conducted to record long-term potential and observe the expressions of Ca^(2+)pathway-related proteins,respectively.Immunohistochemistry was applied to analyze the expression of relevant markers in neuronal damage,inflammation,and white matter injury.Results:The figures showed that spatial memory impairment was detected in Ng cKO mice,and a sharp decline of cerebral blood flow and an impairment of progressive spatial memory were observed in BCAS
Huawei LinJiayong ZhangYaling DaiHuanhuan LiuXiaojun HeLewen ChenJing TaoChaohui LiWeilin Liu
Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the dendritic processes,particularly in post-synaptic compartments,but also in the cytosolic compartment,being likely involved in the regulation of the intracellular calcium-calmodulin signaling pathway (Represa et al.,1990).In the last decade,a plethora of studies have demonstrated that cerebrospinal fluid (CSF) Ng is increased in AD patients and in individuals with an ADlike CSF profile (Kester et al.,2015a).This increase seems to be disease-specific because other neurodegenerative conditions including frontotemporal dementia,Lewy body dementia,Parkinson’s disease,progressive supranuclear palsy,multiple system atrophy or Huntington’s disease,present CSF Ng concentrations similar to controls (Wellington et al.,2016).Ng levels in CSF appear to be elevated in mild cognitive impairment (MCI)-affected individuals who progress to AD and are highly related to memory and cognitive function (Kester et al.,2015a;Tarawneh et al.,2016),which indicates that this protein may serve as an early AD biomarker with diagnostic utility in pre-dementia disease stages,and with prognostic utility to predict cognitive decline and MCI-to-AD conversion.