Abstract
BackgroundAlzheimer’s disease (AD) is responsible for 60–70% of all cases of dementia. On the other hand, the tap water consumed by hundreds of millions of people has been fluoridated to prevent tooth decay. However, little is known about the influence of fluoride on the expression of APP and subsequent changes in learning and memory and neuropathological injury. Our aim here was to determine whether exposure to fluoride aggravates the neuropathological lesions in mice carrying the amyloid precursor protein (APP)/presenilin1 (PS1) double mutation.MethodsThese transgenic or wide-type (WT) mice received 0.3 ml of a solution of fluoride (0.1 or 1 mg/ml, prepared with NaF) by intragastric administration once each day for 12 weeks. The learning and memory of these animals were assessed with the Morris water maze test. Senile plaques, ionized calcium binding adaptor molecule 1 (Iba-1), and complement component 3 (C3) expression were semi-quantified by immunohistochemical staining; the level of Aβ42 was detected by Aβ42 enzyme-linked immunosorbent assays (ELISAs); the levels of synaptic proteins and enzymes that cleave APP determined by Western blotting; and the malondialdehyde (MDA) content and activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) measured by biochemical procedures.ResultsThe untreated APP mice exhibited a decline in learning and memory after 12 weeks of fluoride treatment, whereas treatment of these some animals with low or high levels of fluoride led to such declines after only 4 or 8 weeks, respectively. Exposure of APP mice to fluoride elevated the number of senile plaques and level of Aβ42, Iba-1, and BACE1, while reducing the level of ADAM10 in their brains. The lower levels of synaptic proteins and enhanced oxidative stress detected in the hippocampus of APP mice were aggravated to fluoride.ConclusionsThese findings indicate that exposure to fluoride, even at lower concentration, can aggravate the deficit in learning and memory and neuropathological lesions of the mice that express the high level of APP.
Highlights
Alzheimer’s disease (AD), a neurodegenerative disorder characterized by progressive memory loss and other cognitive impairments [1], is responsible for 60–70% of all cases of dementia [2]
Spatial learning and memory of mice After 1 week of exposure to fluoride, there were no significant differences in the escape latency, number of platform crossings, and time spent at the original position of the platforms between the different groups of mice (Fig. 3a, b)
The findings indicate that fluoride might promote BACE1 and suppress ADAM10 activity, thereby resulting in more Aβ production in the brains of the animals carrying the amyloid precursor protein (APP) mutation
Summary
Alzheimer’s disease (AD), a neurodegenerative disorder characterized by progressive memory loss and other cognitive impairments [1], is responsible for 60–70% of all cases of dementia [2]. Clear evidence indicates that accumulation of Aβ, a 4-kDa polypeptide formed by proteolytic cleavage of amyloid precursor protein (APP) by β- and γ-secretases, is a primary pathogenic event [5, 6], leading to synaptic and neuronal loss, oxidative damage, and multiple inflammatory responses [7,8,9]. Alzheimer’s disease (AD) is responsible for 60–70% of all cases of dementia. Our aim here was to determine whether exposure to fluoride aggravates the neuropathological lesions in mice carrying the amyloid precursor protein (APP)/presenilin (PS1) double mutation
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