Amelioration of Behavioral Impairments and Neuropathology by Antiepileptic Drug Topiramate in a Transgenic Alzheimer's Disease Model Mice, APP/PS1

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease that is the main cause of dementia in the elderly. The aggregation of β-amyloid peptides is one of the characterizing pathological changes of AD. Topiramate is an antiepileptic drug, which in addition, is used in the treatment of many neuropsychiatric disorders. In this study, the therapeutic effects of topiramate were investigated in a transgenic mouse model of cerebral amyloidosis (APP/PS1 mice). Before, during, and after topiramate treatment, behavioral tests were performed. Following a treatment period of 21 days, topiramate significantly ameliorated deficits in nest-constructing capability as well as in social interaction. Thereafter, brain sections of mice were analyzed, and a significant attenuation of microglial activation as well as β-amyloid deposition was observed in sections from topiramate-treated APP/PS1 mice. Therefore, topiramate could be considered as a promising drug in the treatment of human AD.

Keywords: APP/PS1 transgenic mouse; Alzheimer’s disease; amyloidosis; topiramate.

Figure 1

Molecular structure of topiramate.

Figure 2

Effect of topiramate treatment on behavioral impairments (social interaction assay). APP/PS1 mice received oral treatment of topiramate for 21 days. Social interaction was determined by a resident-intruder assay (see Materials and methods). (A) As baseline controls of social interaction, APP/PS1 mice had less interactive behavioral events and more independent behavioral events together with introduced intruder mice compared with naïve mice. Following treatment, increased behavioral events were observed in the topiramate group in comparison with the controls. (B) We observed no significant change in the distance traveled both in the control and topiramate-treated group.

Figure 3

Effect of topiramate treatment on behavioral impairments (nest construction assay). APP/PS1 mice received oral treatment of topiramate for 21 days. Together with naïve mice, they were assessed for nesting behavior. Nest construction was explored with paper towel material using a three-point scaling system (see Materials and methods) in naïve and APP/PS1 mice. (A) No significant difference between the topiramate and the control group could be observed right at the beginning of treatment, namely at Day 1. (B) At Day 11, a non-significant increase of the nesting score was observed in the topiramate-treated group. (C) A significant difference between the topiramate and control groups was observed after 21 days of treatment (p < 0.05).

Figure 4

Effect of topiramate on β-amyloid deposition and microglial activation. APP/PS1 were either treated with topiramate or carboxymethylcellulose (CMC) (used as vehicle for control group). After 21 days of treatment by gavage, brains from transgenic mice and their untreated littermates were analyzed by immunohistochemistry. Cells and plaque count as well as arithmetic means of the immunoreactivity (IR) area are represented in different graphs. The unpaired t-test was used to calculate the differences of plaque/cell counts and area percentages between the treatment group and control, with significance levels set at p < 0.05. (A) Topiramate significantly reduced the number of amyloid plaques in the cortex of APP/PS1. (C) A reduction of plaque number was also observed in the hippocampus of mice. (B,D) IR percentages of amyloid plaques were significantly reduced in both the hippocampus and cortex after topiramate treatment. (E,F) In APP/PS1 mice treated with topiramate, the Iba-1 IR was significantly reduced in both the cortex and hippocampus.

Figure 5

Effect of topiramate on amyloid beta (Aβ) accumulation and inflammation activation. Images show the deposition of Aβ and microglial activation in different treatment groups. (A,B) APP/PS1 mice from the control group showed larger Aβ plaques in the cortex (A) in comparison to the topiramate-treated group (B). (C,D) Microglia staining for Iba-1 showed higher cell numbers and a larger IR area of microglia surrounding the plaques in the cortex of the control mice. (E,F) The hippocampus of non-treated mice showed larger Aβ plaques in comparison to treatment (topiramate). (G,H) Results from microglia activation by targeting Iba-1 showed that the cells were clustered around amyloid plaques and distributed throughout the hippocampus in both the control and topiramate groups.