Ligature-induced periodontitis in a transgenic mouse model of Alzheimer's disease dysregulates neuroinflammation, exacerbates cognitive impairment, and accelerates amyloid pathology

被引：0
作者：
Jimenez-Harrison, Daniela M. [1 ,2 ,3 ]
Butler, Michael J. [1 ]
Ijaz, Haanya [1 ]
Alsabbagh, Rami [4 ,5 ]
Bettes, Menaz N. [1 ]
Demarsh, James W. [1 ]
Mackey-Alfonso, Sabrina E. [1 ,2 ,3 ]
Muscat, Stephanie M. [1 ,6 ]
Alvarez, Bryan D. [1 ,3 ]
Blackwell, Jade A. [1 ,7 ]
Taylor, Ashton [1 ]
Jantsch, Jeferson [1 ]
Sanchez, Andrew A. [1 ]
Peters, Sarah B. [5 ,6 ]
Barrientos, Ruth M. [1 ,6 ,8 ,9 ]
机构：
[1] Ohio State Univ, Inst Behav Med Res, 460 Med Ctr Dr, Columbus, OH 43210 USA
[2] Ohio State Univ, Coll Med, Med Scientist Training Program, Columbus, OH USA
[3] Ohio State Univ, Neurosci Grad Program, Columbus, OH USA
[4] Ohio State Univ, Coll Dent, Div Periodontol, Columbus, OH USA
[5] Ohio State Univ, Coll Dent, Div Biosci, Columbus, OH USA
[6] Ohio State Univ, Dept Neurosci, Coll Med, Columbus, OH USA
[7] Ohio State Univ, MCDB Grad Program, Columbus, OH USA
[8] Ohio State Univ, Chron Brain Injury Program, Discovery Themes Initiat, Columbus, OH USA
[9] Ohio State Univ, Coll Med, Dept Psychiat & Behav Hlth, Columbus, OH USA
来源：
BRAIN BEHAVIOR & IMMUNITY-HEALTH | 2025年 / 44卷
关键词：
MODIFIABLE RISK-FACTORS; SYNAPTIC DYSFUNCTION; PERIRHINAL CORTICES; SPATIAL MEMORY; BONE LOSS; INFLAMMATION; INFECTION; PROTEIN; CORTEX; BRAIN;
D O I：
10.1016/j.bbih.2025.100969
中图分类号：
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号：
100102 ;
摘要：
A growing body of literature has identified periodontal disease among the modifiable risk factors for Alzheimer's disease (AD), but the mechanisms underlying this relationship is unknown. This study investigated this relationship using a ligature-induced preclinical periodontitis (Pd) model in non-transgenic (non-Tg) and 3xTgAD mice. We found that ligature placement caused significant alveolar bone loss, with 3xTg-AD mice exhibiting exacerbated bone loss, suggesting AD-related genetic risk may amplify disease progression. Pd induced robust local inflammatory gene expression in both genotypes, but 3xTg-AD mice indicated a dysregulated immune response. Cognitive deficits were observed only in Pd-afflicted 3xTg-AD mice, specifically in hippocampus-mediated spatial memory and perirhinal cortex-mediated object recognition memory, while non-Tg mice remained unaffected. Neuroinflammatory responses varied by brain region, with the hippocampus and prefrontal cortex (PFC) showing the most pronounced changes. In these regions, 3xTg-AD mice exhibited significantly altered cytokine gene expression compared to non-Tg mice, particularly at later time points. Synaptic markers revealed vulnerabilities in 3xTg-AD mice, including reduced baseline Syp expression and dysregulated Synpo post-ligature. Pd transiently reduced glutamate receptor gene expression in both genotypes, with non-Tg mice showing persistent changes, potentially linked to preserved memory. Pd also accelerated amyloid-beta (A beta) deposition and sustained neurodegeneration in 3xTg-AD mice. Overall, this study shows that combining Pd and AD-related genetic risk exacerbates inflammation, cognitive impairment, synaptic dysfunction, A beta pathology, and neurodegeneration. Neither insult alone was sufficient to produce these effects, highlighting the synergistic impact. These findings emphasize the need to explore anti-inflammatory interventions and downstream mechanisms to mitigate the confluence of these diseases.
引用
收藏
页数：17
相关论文
共 131 条
[1]  
Abe T., Hajishengallis G., Optimization of the ligature-induced periodontitis model in mice, J. Immunol. Methods, 394, pp. 49-54, (2013)
[2]  
Abu-Amer Y., IL-4 abrogates osteoclastogenesis through STAT6-dependent inhibition of NF-kappaB, J. Clin. Investig., 107, pp. 1375-1385, (2001)
[3]  
Agarwal S., Tannenberg R.K., Dodd P.R., Reduced expression of the inhibitory synapse Scaffolding protein gephyrin in alzheimer's disease, J. Alzheim. Dis., 14, pp. 313-321, (2008)
[4]  
Aggleton J.P., Albasser M.M., Aggleton D.J., Poirier G.L., Pearce J.M., Lesions of the rat perirhinal cortex spare the acquisition of a complex configural visual discrimination yet impair object recognition, Behav. Neurosci., 124, pp. 55-68, (2010)
[5]  
Ai R., Li D., Shi L., Zhang X., Ding Z., Zhu Y., He Y., Periodontitis induced by orthodontic wire ligature drives oral microflora dysbiosis and aggravates alveolar bone loss in an improved murine model, Front. Microbiol., 13, (2022)
[6]  
Akiyama H., Barger S., Barnum S., Bradt B., Bauer J., Cole G.M., Cooper N.R., Eikelenboom P., Emmerling M., Fiebich B.L., Finch C.E., Frautschy S., Griffin W.S., Hampel H., Hull M., Landreth G., Lue L., Mrak R., Mackenzie I.R., McGeer P.L., O'Banion M.K., Pachter J., Pasinetti G., Plata-Salaman C., Rogers J., Rydel R., Shen Y., Streit W., Strohmeyer R., Tooyoma I., Van Muiswinkel F.L., Veerhuis R., Walker D., Webster S., Wegrzyniak B., Wenk G., Wyss-Coray T., Inflammation and Alzheimer's diseas
[7]  
Alzheimer's Association, 2024 Alzheimer's disease facts and figures, Alzheimers Dement, 20, pp. 3708-3821, (2024)
[8]  
Amar S., Gokce N., Morgan S., Loukideli M., Van Dyke T.E., Vita J.A., Periodontal disease is associated with brachial artery endothelial dysfunction and systemic inflammation, Arterioscler. Thromb. Vasc. Biol., 23, pp. 1245-1249, (2003)
[9]  
Balducci C., Santamaria G., La Vitola P., Brandi E., Grandi F., Viscomi A.R., Beeg M., Gobbi M., Salmona M., Ottonello S., Forloni G., Doxycycline counteracts neuroinflammation restoring memory in Alzheimer's disease mouse models, Neurobiol. Aging, 70, pp. 128-139, (2018)
[10]  
Bao J., Li L., Zhang Y., Wang M., Chen F., Ge S., Chen B., Yan F., Periodontitis may induce gut microbiota dysbiosis via salivary microbiota, Int. J. Oral Sci., 14, (2022)
12345678910