Atorvastatin in improvement of cognitive impairments caused by amyloid β in mice: involvement of inflammatory reaction.

Liandong Zhao,Ling Chen,Wenhui Zhi,Guoxi Li,Jun Yin,Chonghui Wang,Qi Wan,Tingting Chen

doi:10.1186/s12883-016-0533-3

Abstract

BackgroundThe production of inflammatory cytokines resulting from amyloid β (Aβ) is associated with the initiation of Alzheimer’s disease (AD). Atorvastatin (ATV) has been reported to improve AD, however, it is unclear how the anti-inflammatory mechanism is linked with its protection against the impairment of spatial cognitive function in AD. The present study was designed to explore what mechanism was possibly involved in the anti-inflammatory pathway in regard to the ATV treatment of AD.MethodsWe used an AD model induced by the administration of Aβ25–35 in male C57BL/6 mice and an in vitro culture system to study the protective effects of ATV on the spatial cognitive deficits, hippocampal long-term potentiation (LTP) impairment and inflammatory reaction.ResultsThe intragastric administration of ATV (5 mg/kg) in Aβ25–35-treated mice significantly ameliorated the spatial cognitive deficits and prevented the LTP impairment in hippocampal CA1. The increased Iba-1 positive cells and inflammatory components in the hippocampus were reduced after the ATV treatment. The anti-inflammatory and LTP protection of ATV were abolished using the replenishment of farnesyl pyrophosphate by the administration of farnesol (FOH). The hippocampal slices culture showed Aβ25–35-induced neurotoxicity in the absence of the presence of ATV. Treatment with ATV (0.5, 1, 2.5 μmol/L) dose-dependently prevented the cell damage in hippocampus induced by Aβ25–35.ConclusionThe administration of ATV ameliorated the cognitive deficits, depressed the inflammatory responses, improved the LTP impairment, and prevents Aβ25-35-induced neurotoxicity in cultured hippocampal neurons. These protective functions of ATV involved the pathway of reducing farnesyl pyrophosphate (FPP).

Highlights

The production of inflammatory cytokines resulting from amyloid β (Aβ) is associated with the initiation of Alzheimer’s disease (AD)
Even though no significant difference was observed in the swim speed, the swimming time spent in the platform quadrant was less in the Aβ-treated animals (P < 0.05)
The results from the Y-maze test demonstrated that the administration of Aβ25–35 significantly decreased the spontaneous alternation behavior (P < 0.01), while the decrease was greatly reversed by the administration of ATV (P < 0.01)

Summary

Introduction

The production of inflammatory cytokines resulting from amyloid β (Aβ) is associated with the initiation of Alzheimer’s disease (AD). The present study was designed to explore what mechanism was possibly involved in the anti-inflammatory pathway in regard to the ATV treatment of AD. The initiation and progression of AD involve many different factors, such as Aβ42/Aβ40 ratio, elevation of cholesterol levels, oxidative stress, alterations in cholinergic nervous system and pro-inflammatory cytokines [2]. Amyloid β (Aβ) peptide has been shown to enhance microglial activation [3], and increase the production of inflammatory cytokines interleukin-1β (IL-1β), interleukin6(IL-6) and tumor necrosis factor-α (TNF-α) [4,5,6]. The pro-inflammatory cytokines exacerbate the disease process, cause neuronal death [10], and disrupt synaptic function and induction of longterm potentiation (LTP) [11].

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Conclusion