Tooth Loss Induces Memory Impairment and Gliosis in App Knock-In Mouse Models of Alzheimer’s Disease

Abstract

Background: Epidemiological studies have shown that tooth loss is associated with Alzheimer’s disease (AD) and dementia. However, the molecular and cellular mechanisms by which tooth loss causes AD remain unclear. Objective: We investigated the effects of tooth loss on memory impairment and AD pathogenesis in App NL - G - F mice. Methods: Maxillary molar teeth on both sides were extracted from 2-month-old AppNL - G - F mice, and the mice were reared for 2 months. The short- and long-term memory functions were evaluated using a novel object recognition test and a passive avoidance test. Amyloid plaques, amyloid-β (Aβ) levels, glial activity, and neuronal activity were evaluated by immunohistochemistry, Aβ ELISA, immunofluorescence staining, and western blotting. The mRNA expression levels of neuroinflammatory cytokines were determined by qRT-PCR analysis. Results: Tooth loss induced memory impairment via an amyloid-cascade-independent pathway, and decreased the neuronal activity, presynaptic and postsynaptic protein levels in both the cortex and hippocampus. Interestingly, we found that tooth loss induced glial activation, which in turn leads to the upregulation of the mRNA expression levels of the neuroinflammation cytokines tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and IL-1β in the hippocampus. We also found that tooth loss activated a stress-activated protein kinase, c-Jun N-terminal kinase (JNK), and increased heat shock protein 90 (HSP90) levels in the hippocampus, which may lead to a glial activation. Conclusion: Our findings suggest that taking care of teeth is very important to preserve a healthy oral environment, which may reduce the risk of cognitive dysfunction.

Tooth Loss-Associated Mechanisms That Negatively Affect Cognitive Function: A Systematic Review of Animal Experiments Based on Occlusal Support Loss and Cognitive Impairment

“…Tooth loss induces the activation of inflammatory cells. Taslima et al ( 2021 ) reported that, after tooth extraction in mice with amyloid precursor protein ( App ) gene knock-in (a mouse model of AD), the numbers of microglia and astrocytes in the hippocampus increased, and a large number of inflammatory cytokines (such as tumor necrosis factor alpha [TNF-α], interleukin-1 [IL-1], and IL-6) were produced, thereby promoting an inflammatory state in neurons in the hippocampus and prefrontal cortex. Early tooth loss can also lead to malnutrition and chronic stress.…”

“…Chronic stress is closely related to inflammation. After teeth extraction, chronic stress activates glial cells and release excess ROS, causing an inflammatory cascade effect in the central nervous system (Taslima et al, 2021 ). Chronic inflammation will also interact with chronic stress and oxidative stress, thereby aggravating nerve damage.…”

Association between Tooth Loss and Alzheimer’s Disease in a Nested Case–Control Study Based on a National Health Screening Cohort

“…Furthermore, it is widely accepted that periodontitis is involved in the synthesis and accumulation of amyloid β, which is a pathologic hallmark of the AD brain [28]. Regardless of amyloid cascade, one experimental study demonstrated that tooth loss induces memory impairment through decreased neuronal activity and glial activation in an AD model [10]. Additionally, it has been suggested that the decreased mastication induced by tooth loss reduces orofacial sensorimotor activity, which eventually inhibits hippocampal neurogenesis [9].…”

“…Tooth loss is a prevalent condition in the elderly population, representing a problem for general health and consequently negatively impacting quality of daily life and cognitive function. Clinical studies have indicated that tooth loss is associated with AD and dementia [5][6][7][8], and experimental studies have demonstrated that tooth loss leads to memory deterioration and loss of neuronal cells [9][10][11]. Although the exact mechanism that links tooth loss with decreased cognitive function has not been determined, some investigators have proposed that tooth loss induces masticatory abnormalities, nutritional changes, and hippocampal damage [12].…”

Sustained high body temperature exacerbates cognitive function and Alzheimer’s disease-related pathologies

“…Inhalation of CO 2 was used to kill the mice, which were then perfused with 0.1 M PBS. The brains of all mouse samples were removed and the cortical tissues of the left hemisphere were snap-frozen in liquid nitrogen and stored at − 80 °C until biochemical analysis, as described previously 49 . The cortical tissues were homogenized in 19 volumes of Tris-buffered saline (TBS; pH 7.6, 10 mM Tris and 150 mM NaCl) containing a phosphatase inhibitor cocktail (Wako Pure Chemical Industries, Osaka, Japan) and a protease inhibitor cocktail (Roche, Mannheim, Germany) and centrifuged at 100,000 rpm for 20 min at 4 °C.…”