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. 2016 Jul;75(7):618-27.
doi: 10.1093/jnen/nlw043. Epub 2016 May 31.

Protective Effects of Forskolin on Behavioral Deficits and Neuropathological Changes in a Mouse Model of Cerebral Amyloidosis

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Free PMC article

Protective Effects of Forskolin on Behavioral Deficits and Neuropathological Changes in a Mouse Model of Cerebral Amyloidosis

Brice Ayissi Owona et al. J Neuropathol Exp Neurol. .
Free PMC article

Abstract

The production of amyloid-β peptides in the brains of patients with Alzheimer disease (AD) may contribute to memory loss and impairments in social behavior. Here, an efficient adenylate cyclase activator, forskolin, was orally administered by gavage (100 mg/kg body weight) to 5-month-old transgenic APP/PS1 mice, which serve as an animal model of cerebral amyloidosis. Analyses of nest construction, sociability, and immunohistochemical features were used to determine the effects of forskolin treatment. After a relatively short term of treatment (10 days), forskolin-treated transgenic mice showed restored nest construction ability (p < 0.05) and their sociability (p < 0.01). There was a reduction of Aβ plaque deposition in the cortex and in the hippocampus. Furthermore, expression of transforming growth factor β, glial fibrillary acidic protein, and Iba-1 in the cortex was reduced in the forskolin-treated group, suggesting regulation of the inflammatory response mediated by activated microglia and astrocytes in the brains of the APP/PS1 mice (p < 0.01). Taken together, these findings suggest that forskolin shows neuroprotective effects in APP/PS1 Tg mice and may be a promising drug in the treatment of patients with AD.

Keywords: APP/PS1 transgenic mice; Alzheimer disease; Cerebral amyloidosis; Forskolin.; β-amyloid.

Figures

Figure 1
Figure 1
Molecular structure of forskolin.
FIGURE 2
FIGURE 2
Effect of forskolin treatment on behavior and sociability impairments. (A, B) APP/PS1 mice were treated for with forskolin in 1% carboxymethylcellulose (CMC) or with CMC alone for 10 days. They were assessed for nesting behavior along with untreated nontransgenic mice. There was no significant difference between the forskolin-treated and control groups at day 1 (n = 6/group) (A). At day 10 there was a significant increase in nesting score in the forskolin-treated compared with control mice (n = 6/group) (p < 0.05) (B). (C) Tested mice spent more time with the stranger 1 mice than empty side; forskolin-treated mice spent more time versus controls (p < 0.01). (D) Times spent in the chamber were not significantly different between control and forskolin group for the preference for social novelty test.
FIGURE 3
FIGURE 3
Effect of forskolin on Aβ deposition. Representative photomicrographs of coronal sections through cortex and hippocampus show reduction of Aβ deposition following forskolin treatment. (A–D) There were numerous, relatively large Aβ plaques in the cortex of a control mouse (A) as compared with the forskolin-treated group (B). There were larger Aβ deposits in the hippocampus of a mouse from the control group (C), as compared with the forskolin-treated group (D). (E–H) Arithmetic means of plaque counts and of IR area percentages. In the cortex of mice treated with forskolin there were fewer Aβ plaques (E) and smaller IR area percentages of Aβ staining (F) than in control mice. The percentage area of Aβ in the hippocampus (H) was also reduced for the forskolin-treated group. *p < 0.05.
FIGURE 4
FIGURE 4
Effect of forskolin on microglia. (AD) Representative photomicrographs of coronal sections through cortex and hippocampus show reduction of microglial activation following treatment with forskolin. Many Iba-1-positive cells are seen in the cortex (A) and hippocampus (C) of control mice. Most of the Iba-1-positive microglia appear to surround Aβ plaques. There are fewer Iba-1-positive cells in the cortex (B) of the forskolin-treated group. There were large numbers of Iba-1-positive cells in the hippocampus, in both control (C) and forskolin-treated group (D). (E, F) The IR area percentage of Iba-1 staining (E) was reduced in the forskolin-treated group (n = 6/group) and in the hippocampus (F). **p < 0.01; *p < 0.05.
FIGURE 5
FIGURE 5
Effect of forskolin on TGF-β IR. (A, B) TGF-β1 IR in the cortex of 5-month-old APP/PS1 transgenic mice. After 10 days of forskolin treatment, TGF-β1 IR was reduced in cortex of treated (B) versus control (A) mice. (C) There was a significant reduction in area of TGF-β1 IR following 10 days of forskolin treatment (n = 6/group). **p < 0.01.
FIGURE 6
FIGURE 6
Double staining of for Aβ and GFAP. (A, B) Representative photomicrographs of coronal section through the cortex of transgenic mice reveal GFAP-positive astrocytes (brown) that appear to be clustered around plaques in a control mouse (A) and in a forskolin-treated mouse (B). Nuclei are stained with hemalum. (C) Representative coronal section shows that many most GFAP-positive astrocytes appear to surround Aβ plaques (blue [fast blue chromogen]). (D) GFAP IR area values in the cortex were less in the forskolin versus the control group (n = 6/group). **p = 0.01.

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