Development of a system to analyze oral frailty associated with Alzheimer's disease using a mouse model

Abstract

The rapid aging of the population makes the detection and prevention of frailty increasingly important. Oral frailty has been proposed as a novel frailty phenotype and is defined as a decrease in oral function coexisting with a decline in cognitive and physical functions. Oral frailty has received particular attention in relation to Alzheimer's disease (AD). However, the pathomechanisms of oral frailty related to AD remain unknown. It is assumed that the mesencephalic trigeminal nucleus (Vmes), which controls mastication, is affected by AD pathology, and as a result, masticatory function may be impaired. To investigate this possibility, we included male 3 × Tg-AD mice and their non-transgenic counterpart (NonTg) of 3–4 months of age in the present study. Immunohistochemistry revealed amyloid-β deposition and excessive tau phosphorylation in the Vmes of 3 × Tg-AD mice. Furthermore, vesicular glutamate transporter 1-immunopositive axon varicosities, which are derived from Vmes neurons, were significantly reduced in the trigeminal motor nucleus of 3 × Tg-AD mice. To investigate whether the AD pathology observed in the Vmes affects masticatory function, we analyzed electromyography of the masseter muscle during feeding. The 3 × Tg-AD mice showed a significant delay in masticatory rhythm compared to NonTg mice. Furthermore, we developed a system to simultaneously record bite force and electromyography of masseter, and devised a new method to estimate bite force during food chewing in mice. Since the muscle activity of the masseter showed a high correlation with bite force, it could be accurately estimated from the muscle activity. The estimated bite force of 3 × Tg-AD mice eating sunflower seeds was predominantly smaller than that of NonTg mice. However, there was no difference in masseter weight or muscle fiber cross-sectional area between the two groups, suggesting that the decreased bite force and delayed mastication rhythm observed in 3 × Tg-AD mice were not due to abnormality of the masseter. In conclusion, the decreased masticatory function observed in 3 × Tg-AD mice was most likely caused by AD pathology in the Vmes. Thus, novel quantitative analyses of masticatory function using the mouse model of AD enabled a comprehensive understanding of oral frailty pathogenesis.

Association of Tooth Loss with Alzheimer’s Disease Tau Pathologies Assessed by Positron Emission Tomography

“…Unlike A␤ depositions, tau fibril formations in specific brain areas were tightly related to the tooth number in AD cases. While postmortem study reported no association between the progression of Braak tau stages and the number of remaining teeth [57], an AD model mouse study has shown A␤ and phosphorylated tau accumulation in Vmes before the appearance of AD pathology in the cerebral cortex [58]. Our data imply the contribution of tooth loss to the tau pathogenesis in the brainstem at prodromal and early clinical stages of AD, although there were no correlations of the tooth number with A␤ PET tracer retentions in this region (Supplementary Figure 3).…”

Comparative data on emotional (psychotic) aggressive biting behavior in mice of ddY strain measured by using two devices; Aggressive response meter and powerlab-compatible type aggressive response meter

“…Additionally, stress associated with maternal separation induces elevated ABB in offspring [3] . Measurements based on the ARM have been cited as evidence of emotional aggression caused by mental irritation in both male and female mice [4 , 5] . The ARM device is also useful for the pharmacological analysis of drugs that reduce aggressive biting behavior [6 , 7] and for the analysis of aggression in histamine N -methyl transferase-deficient mice [8] .…”

Pre-Adolescent Diet Normalization Restores Cognitive Function in Young Mice

“…Furthermore, animal studies have reported cognitive declines associated with decreased mastication [15,16]. Three primary methods, namely molar extraction, soft diet, and bite raise, have been used to develop laboratory models (mainly of rodents) of reduced mastication [17].…”