These results suggest that rifampicin is a promising oligomer-targeting medicine and can prevent neurodegenerative dementia when administered early before the neurodegeneration. Furthermore, when orally administered to APP- and tau-transgenic (Tg) mice, rifampicin reduced Aβ and tau oligomers in the brain and improved the cognition of the mice ( Umeda et al., 2016). We previously demonstrated that a well-known antibiotic, rifampicin, inhibited the oligomerization of Aβ, tau, and α-synuclein in vitro and that the activity was specific to pathological amyloidogenic proteins but not to physiologically assembling proteins ( Umeda et al., 2016). The treatment should be started early, before the neurodegeneration proceeds, and the drug target should be set to the toxic oligomers. These failures are primarily attributed to two main reasons: the late timing of medication and the wrong drug target. Many drug candidates have been developed, but most have failed to show beneficial effects on patients’ cognition in clinical trials. Tau oligomers ( Maeda and Takashima, 2019 Hill et al., 2020) and α-synuclein oligomers ( Bengoa-Vergniory et al., 2017 Kayed et al., 2020) are also suggested to play a crucial role in the pathogenesis of tauopathy and α-synucleinopathy, respectively.ĭespite the vigorous efforts of researchers and pharmaceutical companies, there is no effective cure for neurodegenerative dementia. For example, synaptic dysfunction, which is assumed an immediate early symptom in AD, is caused by soluble Aβ oligomers ( Cline et al., 2018 Li and Selkoe, 2020), and Aβ oligomers trigger the pathological cascade of AD including tau hyperphosphorylation, glial activation, and neuronal loss ( Tomiyama et al., 2010 Cline et al., 2018). While these inclusions are helpful for the differential diagnosis of neurodegenerative diseases, accumulating evidence indicates that the real causal culprit of the disease is smaller, soluble oligomers of the proteins. These proteins tend to self-aggregate into insoluble fibrils with the β-sheet structure leading to the formation of characteristic pathological inclusions in the brain, such as senile plaques composed of Aβ, neurofibrillary tangles of hyperphosphorylated tau, and Lewy bodies of phosphorylated α-synuclein. These disorders are characterized by the cerebral accumulation of disease-specific amyloidogenic proteins: Aβ and tau in AD, tau or TDP-43 in FTD, and α-synuclein in DLB and PD. Parkinson’s disease (PD) is also known to pose dementia when its pathologies spread into the cerebral cortex.
Neurodegenerative dementia is defined as neurodegenerative diseases with a main clinical symptom of dementia, which includes Alzheimer’s disease (AD), frontotemporal dementia (FTD), and dementia with Lewy bodies (DLB). Our findings may provide a feasible means for the prevention of neurodegenerative dementia that targets toxic oligomers. These results show the advantages of this combinatorial medicine with regards to safety and effectiveness over single-drug rifampicin. Furthermore, the combination showed a synergistic effect in ameliorating mouse cognition.
Notably, resveratrol alone and the combinatorial medicine, but not rifampicin alone, enhanced the levels of brain-derived neurotrophic factor (BDNF) and its precursor, pro-BDNF, in the hippocampus. The plasma levels of liver enzymes, which reflect hepatic injury and normally increase by rifampicin treatment, remained normal by the combination treatment. Compared with rifampicin and resveratrol alone, the combinatorial medicine significantly improved mouse cognition, reduced amyloid oligomer accumulation, and recovered synaptophysin levels in the hippocampus. The mixture was intranasally administered to APP-, tau-, and α-synuclein-transgenic mice, and their memory and oligomer-related pathologies were evaluated. In the present study, to explore more effective and safer medications for dementia, we tested the drug combination of rifampicin and resveratrol, which is a multifunctional natural polyphenol with the potential to antagonize the adverse effects of rifampicin. Previously we demonstrated that oral or intranasal rifampicin improved the cognition of APP-, tau-, and α-synuclein-transgenic mice by reducing the amount of Aβ, tau, and α-synuclein oligomers in the brain. 1Department of Translational Neuroscience, Osaka City University Graduate School of Medicine, Osaka, JapanĪmyloidogenic protein oligomers are thought to play an important role in the pathogenesis of neurodegenerative dementia, including Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies.Tomohiro Umeda 1, Ayumi Sakai 1, Keiko Shigemori 1, Ayumi Yokota 1, Toru Kumagai 2 and Takami Tomiyama 1,2*