Abstract
Amyloidogenic 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. 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. 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. The mixture was intranasally administered to APP-, tau-, and α-synuclein-transgenic mice, and their memory and oligomer-related pathologies were evaluated. 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 plasma levels of liver enzymes, which reflect hepatic injury and normally increase by rifampicin treatment, remained normal by the combination treatment. 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. Furthermore, the combination showed a synergistic effect in ameliorating mouse cognition. These results show the advantages of this combinatorial medicine with regards to safety and effectiveness over single-drug rifampicin. Our findings may provide a feasible means for the prevention of neurodegenerative dementia that targets toxic oligomers.
Highlights
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)
We previously demonstrated that a wellknown 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)
To explore more effective and safer medicines than rifampicin alone, we tested the therapeutic effects of rifampicin and resveratrol combination using four kinds of mouse models of neurodegenerative dementia
Summary
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). Intranasal Rifampicin and Resveratrol Combination accumulation of disease-specific amyloidogenic proteins: Aβ and tau in AD, tau or TDP-43 in FTD, and α-synuclein in DLB and PD 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. 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. Tau oligomers (Maeda and Takashima, 2019; Hill et al, 2020) and α-synuclein oligomers (Bengoa-Vergniory et al, 2017; Kayed et al, 2020) are suggested to play a crucial role in the pathogenesis of tauopathy and α-synucleinopathy, respectively
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