Research Article: Amelioration of cognitive impairments in APPswe/PS1dE9 mice is associated with metabolites alteration induced by total salvianolic acid

Date Published: March 30, 2017

Publisher: Public Library of Science

Author(s): Li Shen, Bing Han, Yuan Geng, Jinhua Wang, Zhengmin Wang, Mingwei Wang, Stephen D Ginsberg.


Total salvianolic acid (TSA) is extracted from salvia miltiorrhiza; however, to date, there has been limited characterization of its effects on metabolites in Alzheimer’s disease model-APPswe/PS1dE9 mice. The main objective of this study was to investigate the metabolic changes in 7-month-old APPswe/PS1dE9 mice treated with TSA, which protects against learning and memory impairment.

APPswe/PS1dE9 mice were treated with TSA (30 mg/kg·d and 60 mg/kg·d, i.p.) and saline (i.p.) daily from 3.5 months old for 14 weeks; saline-treated (i.p.) WT mice were included as the controls. The effects of TSA on learning and memory were assessed by a series of behavioral tests, including the NOR, MWM and step-through tasks. The FBG and plasma lipid levels were subsequently assessed using the GOPOD and enzymatic color methods, respectively. Finally, the concentrations of Aβ42, Aβ40 and metabolites in the hippocampus of the mice were detected via ELISA and GC-TOF-MS, respectively.

At 7 months of age, the APPswe/PS1dE9 mice treated with TSA exhibited an improvement in the preference index (PI) one hour after the acquisition phase in the NOR and the preservation of spatial learning and memory in the MWM. Treatment with TSA substantially decreased the LDL-C level, and 60 mg/kg TSA decreased the CHOL level compared with the plasma level of the APPswe/PS1dE9 group. The Aβ42 and Aβ40 levels in the hippocampus were decreased in the TSA-treated group compared with the saline-treated APPswe/PS1dE9 group. The regulation of metabolic pathways relevant to TSA predominantly included carbohydrate metabolism, such as sorbitol, glucose-6-phosphate, sucrose-6-phosphate and galactose, vitamin metabolism involved in cholecalciferol and ascorbate in the hippocampus.

TSA induced a remarkable amelioration of learning and memory impairments in APPswe/PS1dE9 mice through the regulation of Aβ42, Aβ40, carbohydrate and vitamin metabolites in the hippocampus and LDL-C and CHOL in the plasma.

Partial Text

Alzheimer’s disease, a widespread type of dementia in elderly individuals, is an age-associated neurodegenerative disease characterized by ongoing episodic memory impairment and progressive cognitive deficiencies [1]. The symptoms are severe and affect work, hobbies and social life. To date, there are approximately 50 million senior patients with AD, and in China, which has a population in excess of one billion, patients with AD comprise more than 5.1 million (World Health Organization, 2012). More than one-half of elders older than 85 years of age experience the pain of AD worldwide [2]. The aging situation is currently grim; thus, research on the preventive medicine is meaningful and extremely urgent for patients with AD to escape from the disorder or ameliorate the scourge of dementia syndromes.

Alzheimer’s disease represents a common type of dementia worldwide. The recent morbidity of AD is greater than ever because of aging and the lack of convincing therapy. Several transgenic mouse lines imitate the age-dependent cognitive impairment of human AD by possessing a high quantity of Aβ in the brains of the mice. AD animal models, such as APPswe/ PS1dE9 mice, accelerate the pathology starting from the age of four months [9]. Traditional cognitive tests associated with the activity of the hippocampus and other brain sections have included the object recognition, MWM and STPA tests, which reflect the neurophysiology of the mice [30]. Based on previous results, cognitive impairments in APP/PS1 mice over 6 months old were observed in the MWM and passive avoidance behavior tasks [31, 32]. The NOR test is a facile behavioral assay with the advantage of little or no stress and needless spatial orientation [33]. A limited number of reports have included the NOR in APP/PS1dE9 transgenic mice in the early period of AD; several papers have illustrated that deficits existed in other transgenic mice related to Aβ at the age of 6–8 months [34], and another study demonstrated that APP/PS1 mice aged 8 months exhibited short-term memory deficits [28]. In our report, the poor exploratory behavior in the NOR elucidated there were deficits in the recognition memory of a short-time in 7-month-old APP/PS1dE9 mice. In this early period of memory impairment, APPswe/PS1dE9 mice were prone to forgetting the object they recently touched. On the other hand, for the APPswe/PS1dE9 mice, perhaps there was less desire to acquaint with the novel object compared with the WT control mice. The next day, the decreased PI of WT control group suggested WT mice could hardly remember the old object they touched 24 hours ago. At that time, no statistical difference of the recognition to the novel object was on account of the shortened gap of PI between APPswe/ PS1dE9 mice and their control mice induced by the slight decline in PI of APPswe/ PS1dE9 mice except for the reduced PI of WT mice 24 hours subsequent to the training. According to such results, a thesis was presented that the impairment of exploratory behavior in the NOR occurred one hour but not 24 hours after the training, which suggested the deficits existed originally in the short-term recognition memory.

In our study, we concluded that TSA comprised a multi-metabolite regulator whose pathway was involved in carbohydrate metabolism and vitamin metabolism in the hippocampus and lipid metabolism in plasma, which could be used in the earlier stages of AD prior to severe Aβ deposition and neurodegeneration. To our knowledge, this investigation comprises the first report that demonstrated TSA may represent a promising therapeutic candidate for AD because of its sustainable protective effects on learning and memory via metabolite regulation, as demonstrated in this study. In the future, second validation detection should be conducted using a targeted approach to confirm the current findings; moreover, the mechanisms of the metabolite alterations remain to be elucidated. In addition, the plasma metabolites in the mice should be investigated. The disadvantage of our study including short of pathological research will be subsequently addressed in more detail.




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