Effects of apoE Deficiency and Occlusal Disharmony on Amyloid-Beta Production and Spatial Memory in Rats

Daisuke Ekuni,Tetsuji Azuma,Takaaki Tomofuji,Koichiro Irie,Yasumasa Endo,Manabu Morita,Kenta Kasuyama,John D Fryer

doi:10.1371/journal.pone.0074966

Abstract

Amyloid-β (Aβ) plays a causative role in Alzheimer’s disease. Apolipoprotein E (apoE) is involved in Aβ accumulation, whereas occlusal disharmony increases Aβ production in the rat hippocampus. The purpose of the present study was to investigate the effects of apoE deficiency and occlusal disharmony on Aβ production and spatial memory. Wild-type (WT) (n = 12) and apoE-deficient [ApoE(−/−)] (n = 12) rats (Sprague-Dawley; 8 weeks old) were used. These rats were randomly divided into four groups of six rats each: two control (C) groups: WT (C-WT) and ApoE [C-ApoE(−/−)], and two occlusal disharmony (D) groups: WT (D-WT) and ApoE [D-ApoE(−/−)]. The C group received no treatment for 8 weeks. In the D group, the maxillary molar cusps were cut off for 8 weeks. The spatial memory of rats was assessed according to their behavioral performance in a radial arm maze. In both genotypes of rats, significant differences in the reference memory, Aβ42 production, β-secretase expression and plasma corticosterone levels were observed between the C and D groups (P < 0.0125). The levels of Aβ42 and glucocorticoid receptor in the C-ApoE(−/−) group were also significantly higher than those in the C-WT group (P < 0.0125). However, no significant differences in these parameters were found between the two genotypes with occlusal disharmony. In conclusion, occlusal disharmony induces cognitive dysfunction and Aβ accumulation in the rat hippocampus, and the effects of occlusal disharmony on Aβ accumulation and cognitive dysfunction were larger than those of apoE deficiency.

Highlights

Alzheimer’s disease (AD), the late-onset form of AD (LOAD), is the most common cause of dementia in individuals older than 60 years of age [1]
Psychological stress induced by occlusal disharmony reversibly induces Aβ40 and Aβ42 accumulation in the rat hippocampus through glucocorticoid signaling [22]. These findings suggest that psychological stress following occlusal disharmony may represent a potential risk factor for AD in addition to apolipoprotein E (apoE)
The purpose of the present study was to investigate the effects of apoE deficiency and occlusal disharmony on Aβ production in the rat hippocampus and spatial memory

Summary

Introduction

Alzheimer’s disease (AD), the late-onset form of AD (LOAD), is the most common cause of dementia in individuals older than 60 years of age [1]. Amyloid-β (Aβ) accumulation and its neurotoxicity in the brain play a causative role in AD [2]. Despite intensive laboratory and clinical research over the last three decades, no effective treatment to delay the onset and progression of AD has been established [5]. Aβ accumulation is a cause and an effect of AD, an imbalance between Aβ production and clearance is caused by other upstream events in all patients with AD, and most of these other causes are currently unknown [5]. One of the strongest causes is inheritance of one or two ε4 alleles of the apolipoprotein E (apoE) gene [6]. ApoE is present in neuritic plaques and neurofibrillary tangles [11], and apoE4-positive AD patients have higher levels of such plaques and tangles than do corresponding AD patients who do not express this apoE allele [12,13,14,15,16]

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