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

Article type: Research Article

Authors: Taslima, Ferdous^a | Jung, Cha-Gyun^{a; *} | Zhou, Chunyu^a | Abdelhamid, Mona^a | Abdullah, Mohammad^a | Goto, Tetsuya^b | Saito, Takashi^c | Saido, Takaomi C.^d | Michikawa, Makoto^{a; *}

Affiliations: [a] Department of Biochemistry, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan | [b] Department of Oral Anatomy & Cell Biology, Graduate School of Medical and Dental Science, Kagoshima University, Kagoshima, Japan | [c] Department of Neurocognitive Science, Institute of Brain Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan | [d] Laboratory for Proteolytic Neuroscience, RIKEN Center for Brain Science, Wako, Japan

Correspondence: [*] Correspondence to: Makoto Michikawa, MD, PhD, Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 Aichi, Japan. Tel.: +81 52 853 8139; Fax: +81 52 841 3480; E-mail: michi@med.nagoya-cu.ac.jp. and Cha-Gyun Jung, PhD, Department of Biochemistry, Graduate School of Medical Sciences, Nagoya City University, 1 Kawasumi, Mizuho-cho, Mizuho-ku, Nagoya 467-8601 Aichi, Japan. Tel.: +81 52 853 8141; Fax: +81 52 841 3480; E-mail: jung@med.nagoya-cu.ac.jp.

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 AppNL-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.

Keywords: Alzheimer’s disease, App^NL-G-Fknock-in mice, chronic stress, glial activation, memory impairment, synapses, tooth loss

DOI: 10.3233/JAD-201055

Journal: Journal of Alzheimer's Disease, vol. 80, no. 4, pp. 1687-1704, 2021