Atorvastatin attenuates the production of IL-1β, IL-6, and TNF-α in the hippocampus of an amyloid β1-42-induced rat model of Alzheimer's disease

Abstract

Background and aim: Amyloid-beta (Aβ) peptide is reported to initiate flexible inflammation in the hippocampus of the human brain in Alzheimer's disease (AD). The present study aimed to investigate the possible effects of atorvastatin on the production of inflammation cytokines in the hippocampus and the potential impacts on behavioral ability, in an AD model.

Methods: We firstly established AD rat models using intracerebroventricular injection of Aβ1-42. A Morris water maze was also performed to determine the spatial learning and memory ability in the AD models. Intracellular staining of interleukin (IL)-1β, IL-6, and tumor necrosis factor alpha was determined using immunohistochemical staining at 6 hours and day 7 after the injection of Aβ.

Results: The escape latency of the atorvastatin-treated AD group (5 mg/kg/d) was significantly shorter than that of AD group on day 3 (41 ± 1.05 seconds versus 47 ± 1.05 seconds, P < 0.01) and day 4 (34 ± 1.25 seconds versus 43 ± 1.01 seconds, P < 0.01) after the beginning of the training. Furthermore, the atorvastatin-treated AD group displayed a significant higher mean number of annulus crossings than did the AD group (2.9 ± 0.5 versus 2.4 ± 0.9, P < 0.05). Fewer injured nerve cells and proliferated glial cells were also demonstrated in the atorvastatin-treated AD group than in the AD group. Of great importance, we demonstrated that IL-1β, IL-6, and tumor necrosis factor alpha were significantly decreased in the atorvastatin-treated AD group than that in the AD group.

Conclusion: Atorvastatin might attenuate the damage of nerve cells and improve learning and memory ability by inhibiting inflammatory response in the progression of AD.

Keywords: amyloid-beta; inflammation; interleukin-1β; interleukin-6; tumor necrosis factor.

Figure 1

Atorvastatin improved the spatial learning and memory of rats impaired by Aβ1-42, using the Morris water maze test. (A) Escape latency onto a hidden platform; (B) probe test; and (C) working memory. Abbreviations: Aβ, amyloid-beta (peptide); AD, Alzheimer’s disease; S, second.

Figure 2

Pathological changes in the hippocampus of rats in each group on day 7 after Aβ injection (original magnification × 400). (A) Control group; (B) atorvastatin control group; (C) AD group; and (D) atorvastatin-treated AD group. Abbreviations: Aβ, amyloid-beta (peptide); AD, Alzheimer’s disease.

Figure 3

Atorvastatin attenuated IL-1β expression in the hippocampus of Aβ1-42-treatedrats. The upper panel shows IL-1 β-positive cells in the rat hippocampus, detected by immunohistochemistry on day 7 after Aβ injection (original magnification x 400). (A) Control group (Group 1); (B) atorvastatin control group (Group 2); (C) AD group (Group 3); and (D) atorvastatin-treated AD group (Group 4). (E) The lower panel shows the counted number of IL-1 β-positive cells in rat hippocampus. Notes: Data are the mean ± SD of each individuals. *P < 0.01. Abbreviations: Aβ, amyloid-beta (peptide); IL, interleukin; AD, Alzheimer’s disease.

Figure 4

Atorvastatin attenuated IL-6 expression in the hippocampus of Aβ1-42-treated rats. The upper panel shows IL-6-positive cells in the rat hippocampus, detected by immunohistochemistry on day 7 after Aβ injection (original magnification x 400). (A) Control group (Group 1); (B) atorvastatin control group (Group 2); (C) AD group (Group 3); and (D) atorvastatin-treated AD group (Group 4). (E) The lower panel shows the counted number of IL-6-positive cells in rat hippocampus. Notes: Data are the mean ± SD of each individuals. *P < 0.01. Abbreviations: IL, interleukin; Aβ, amyloid-beta (peptide); AD, Alzheimer’s disease.

Figure 5

Atorvastatin attenuated TNF-α expression in the hippocampus of Aβ1-42-treated rats. The upper panel shows TNF-α-positive cells in the rat hippocampus, detected by immunohistochemistry on day 7 after Aβ injection (original magnification × 400). (A) Control group (Group 1); (B) atorvastatin control group (Group 2); (C) AD group (Group 3); and (D) atorvastatin-treated AD group (Group 4). (E) The lower panel shows the counted number of TNF-α-positive cells in rat hippocampus. Notes: Data are the mean ± SD of each individuals. *P < 0.01. Abbreviations: TNF-α, tumor necrosis factor alpha; Aβ, amyloid-beta (peptide); AD, Alzheimer’s disease.