Effects of early tooth loss on chronic stress and progression of neuropathogenesis of Alzheimer's disease in adult Alzheimer's model AppNL-G-F mice.

Introduction: Alzheimer's disease (AD), the most common neurodegenerative disease, is characterized by accumulated amyloid-ß (Aß) plaques, aggregated phosphorylated tau protein, gliosis-associated neuroinflammation, synaptic dysfunction, and cognitive impairment. Many cohort studies indicate that tooth loss is a risk factor for AD. The detailed mechanisms underlying the association between AD and tooth loss, however, are not yet fully understood. Methods: We explored the involvement of early tooth loss in the neuropathogenesis of the adult AppNL-G-F mouse AD model. The maxillary molars were extracted bilaterally in 1-month-old male mice soon after tooth eruption. Results: Plasma corticosterone levels were increased and spatial learning memory was impaired in these mice at 6 months of age. The cerebral cortex and hippocampus of AD mice with extracted teeth showed an increased accumulation of Aß plaques and phosphorylated tau proteins, and increased secretion of the proinflammatory cytokines, including interleukin 1ß (IL-1ß) and tumor necrosis factor α (TNF-α), accompanied by an increased number of microglia and astrocytes, and decreased synaptophysin expression. AD mice with extracted teeth also had a shorter lifespan than the control mice. Discussion: These findings revealed that long-term tooth loss is a chronic stressor, activating the recruitment of microglia and astrocytes; exacerbating neuroinflammation, Aß deposition, phosphorylated tau accumulation, and synaptic dysfunction; and leading to spatial learning and memory impairments in AD model mice.

Maternal chewing improves prenatal stress-induced cognitive deficit and anxiety-like behavior associated with alterations of the apoptotic response and serotonin pathway in mouse offspring.

OBJECTIVE: To examine whether maternal chewing affects prenatal stress-induced behavioral alternations associated with the changes in apoptosis-related proteins and serotonin pathway of the mouse offspring. DESIGN: Pregnant mice were assigned to control, stress, and stress/chewing groups. Stress mice were placed in restraint tubes, from gestational day 12 until parturition. Stress/chewing mice were given a wooden stick for chewing during stress period. Morris water maze and hole-board tests were applied for behavioral alterations in one-month-old male pups. Hippocampal mRNA expression of B-cell lymphoma 2 (Bcl-2) and Bcl-2 associated X protein (Bax) was analyzed by quantitative real-time PCR. Serotonin and tryptophan hydroxylase expression level in the dorsal raphe nucleus was investigated immunohistochemically. RESULTS: Prenatal stress impaired the spatial learning, induced anxiety-like behavior, increased the ratio of hippocampal Bax/Bcl-2 expression, and decreased the expression of serotonin and tryptophan hydroxylase in dorsal raphe nucleus of the offspring. Maternal chewing ameliorated prenatal stress-induced cognitive impairment, anxiety-like behavior, and attenuated the increased ratio of hippocampal Bax/Bcl-2 expression, and the downregulated serotonin signaling in dorsal raphe nucleus of the offspring. CONCLUSIONS: Our results indicate that maternal chewing could improve prenatal stress-related anxiety-like behavior and cognitive impairment in mouse offspring, at least in part by affecting hippocampal apoptotic response and central serotonin pathway.