Periodontitis induced by bacterial infection exacerbates features of Alzheimer’s disease in transgenic mice

Abstract

Periodontitis is a localized infectious disease caused by periodontopathic bacteria, such as Porphyromonas gingivalis. Recently, it has been suggested that bacterial infections may contribute to the onset and the progression of Alzheimer’s disease (AD). However, we do not have any evidence about a causative relationship between periodontitis and AD. In this study, we investigated by using a transgenic mouse model of AD whether periodontitis evoked by P. gingivalis modulates the pathological features of AD. Cognitive function was significantly impaired in periodontitis-induced APP-Tg mice, compared to that in control APP-Tg mice. Levels of Amiloid β (Aβ) deposition, Aβ40, and Aβ42 in both the hippocampus and cortex were higher in inoculated APP-Tg mice than in control APP-Tg mice. Furthermore, levels of IL-1β and TNF-α in the brain were higher in inoculated mice than in control mice. The levels of LPS were increased in the serum and brain of P. gingivalis-inoculated mice. P. gingivalis LPS-induced production of Aβ40 and Aβ42 in neural cell cultures and strongly enhanced TNF-α and IL-1β production in a culture of microglial cells primed with Aβ. Periodontitis evoked by P. gingivalis may exacerbate brain Aβ deposition, leading to enhanced cognitive impairments, by a mechanism that involves triggering brain inflammation.

TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

“…Acute intraperitoneal LPS injection also increased tau phosphorylation in the hippocampal neurons of C57BL/6 mice (126,127). Furthermore, periodontitis evoked by inoculation of Porphyromonas gingivalis exacerbated brain Aβ deposition and cognitive deficits in an AD mouse model (J20 PDGF-APPSw-Ind mice) (128). Repeated intraperitoneal injection of LPS derived from Porphyromonas gingivalis induced cognitive deficits, intraneuronal Aβ accumulation, microglial activation, and increases in IL-1β in middle-aged (12 months) wild-type C57BL/6 mice but not in young (2 months) mice (129).…”

Is there a link between genetic defects in the complement cascade andPorphyromonas gingivalisin Alzheimer’s disease?

“…In addition, P. gingivalis activates complement in the absence of Aβ in the brain [23]. Complement activation following bacterial entry into the brain is to be expected, but this observation may also explain memory impairment possibly through intercommunication with toll-like receptor (TLR) activation, lipopolysaccharide (LPS) (a TLR4 agonist) and complement activation [49,[76][77][78]. Collectively, they may also cause loss of synapses [65,68] if CR1 functionality is suppressed by its polymorphism or via immune evasion strategies of bacteria like P. gingivalis.…”

How masticatory function and periodontal disease relate to senile dementia

“…1). Mice in which periodontal disease was induced experimentally, as mentioned earlier, showed reduced cognitive function and increased deposition of amyloid ␤-protein in the hippocampus and cerebral cortex [41]. Such findings suggest that the oral function and oral hygiene condition of elderly individuals may affect the status of dementia.…”

“…In a recent study, we examined AD model mice (J20 mice) with periodontal disease caused by oral inoculation of P. gingivalis. Compared to mice not inoculated with the bacteria, the mice with periodontal disease showed lower maintenance of cognitive function, increased deposition of senile plaques in the hippocampus and cortex of the brain tissue, and increased levels of interleukin 1␤ and TNF-␣ in the brain tissue [41]. These findings suggest the possibility that persistent infection in a localized area of the host, such as periodontal tissue, and the resulting inflammatory response may spill over to the whole body, including the brain, and may be involved in systemic inflammation and the development of AD [42].…”