Rifampicin is a candidate preventive medicine against amyloid-β and tau oligomers

Abstract

Amyloid-β, tau, and α-synuclein, or more specifically their soluble oligomers, are the aetiologic molecules in Alzheimer's disease, tauopathies, and α-synucleinopathies, respectively. These proteins have been shown to interact to accelerate each other's pathology. Clinical studies of amyloid-β-targeting therapies in Alzheimer's disease have revealed that the treatments after disease onset have little benefit on patient cognition. These findings prompted us to explore a preventive medicine which is orally available, has few adverse effects, and is effective at reducing neurotoxic oligomers with a broad spectrum. We initially tested five candidate compounds: rifampicin, curcumin, epigallocatechin-3-gallate, myricetin, and scyllo-inositol, in cells expressing amyloid precursor protein (APP) with the Osaka (E693Δ) mutation, which promotes amyloid-β oligomerization. Among these compounds, rifampicin, a well-known antibiotic, showed the strongest activities against the accumulation and toxicity (i.e. cytochrome c release from mitochondria) of intracellular amyloid-β oligomers. Under cell-free conditions, rifampicin inhibited oligomer formation of amyloid-β, tau, and α-synuclein, indicating its broad spectrum. The inhibitory effects of rifampicin against amyloid-β and tau oligomers were evaluated in APPOSK mice (amyloid-β oligomer model), Tg2576 mice (Alzheimer's disease model), and tau609 mice (tauopathy model). When orally administered to 17-month-old APPOSK mice at 0.5 and 1 mg/day for 1 month, rifampicin reduced the accumulation of amyloid-β oligomers as well as tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent manner. In the Morris water maze, rifampicin at 1 mg/day improved memory of the mice to a level similar to that in non-transgenic littermates. Rifampicin also inhibited cytochrome c release from the mitochondria and caspase 3 activation in the hippocampus. In 13-month-old Tg2576 mice, oral rifampicin at 0.5 mg/day for 1 month decreased amyloid-β oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation, but not amyloid deposition. Rifampicin treatment to 14-15-month-old tau609 mice at 0.5 and 1 mg/day for 1 month also reduced tau oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent fashion, and improved the memory almost completely at 1 mg/day. In addition, rifampicin decreased the level of p62/sequestosome-1 in the brain without affecting the increased levels of LC3 (microtubule-associated protein light chain 3) conversion, suggesting the restoration of autophagy-lysosomal function. Considering its prescribed dose and safety in humans, these results indicate that rifampicin could be a promising, ready-to-use medicine for the prevention of Alzheimer's disease and other neurodegenerative diseases.

Pelargonidin improves memory deficit in amyloid β25-35 rat model of Alzheimer’s disease by inhibition of glial activation, cholinesterase, and oxidative stress

“…Increased oxidative stress at initial stages of neurotoxic conditions is also associated with activation of autophagylysosomal system [55,56] that could be beneficial and protective per se. Meanwhile, Pickford et al have shown decreased autophagy in addition to accelerated Ab aggregation in the brain of mice model of AD [57].…”

Preventive Effect of Rifampicin on Alzheimer Disease Needs at Least 450 mg Daily for 1 Year: An FDG-PET Follow-Up Study

“…However, the dose of rifampicin significantly influenced SUVR change in multiple regression analysis in Group B (Table 3). The oral administration of 1.0 mg/day was more effective than 0.5 mg/day in a mouse model, indicating a dose-dependent effect of rifampicin on AD pathology [8]. A dose of 300 mg/day has little effect on mild-to-moderate AD [12, 13].…”

“…The precise mechanism of the preventive effect of rifampicin on the pathological process of AD was thoroughly investigated in vitro [18] and in vivo [8, 19]. According to these studies, rifampicin has a versatile action to prevent the pathological process of AD.…”

“…As for amyloid-β, its oligomer has been regard ed as a toxic and pathogenic protein [20, 21]. Rifampicin inhibits its oligomerization to produce monomer; however, it fails to decrease amyloid deposition [8]. It rather promotes the growth of senile plaque by providing monomers that form less toxic insoluble fibrils [8].…”

“…Recently, Umeda et al [8] have reported that rifampicin, a well-known antibiotic, inhibited amyloid-β oligomerization and tau hyperphosphorylation in mouse models and improved the memory in the Morris water maze. The findings in mouse models indicated that rifampicin could serve as a promising available medicine for the prevention of AD.…”