Neurodegenerative dementia, which includes Alzheimer’s disease, frontotemporal dementia, and dementia with Lewy bodies, accounts for more than 80% of dementia population. In the brain of patients, characteristic abnormal structures composed of fibrillar aggregates of specific proteins are commonly observed. In Alzheimer’s disease, two proteins, amyloid β (Aβ) and tau, form extracellular and intracellular inclusions called ‘senile plaques’ and ‘neurofibrillary tangles’, respectively. In frontotemporal dementia, either tau or TDP-43 accumulates within cells to display their own inclusions. In dementia with Lewy bodies, α-synuclein is the responsible protein to constitute intracellular inclusions called ‘Lewy bodies’.

While these inclusions were previously assumed to cause neurodegeneration, a current consensus is that the real culprit is soluble oligomers of the etiologic proteins rather than insoluble fibrils. Aging, genetic mutations, and altered metabolism affect the degradation and clearance of the toxic oligomers, leading to their accumulation in the brain. Accumulated oligomers are then sequestered and structurally changed into less harmful insoluble fibrils, resulting in the formation of inclusions, i.e. senile plaques, neurofibrillary tangles, and Lewy bodies. This sequestration system is, however, to be saturated, and oligomers overflowed the inclusions initiate the pathological cascade to neurodegeneration. In Alzheimer’s disease, Aβ oligomers trigger tau hyperphosphorylation to generate tau oligomers that attack neurons (Fig. 1). In frontotemporal dementia, tau pathology proceeds without Aβ. Once neuronal damage reaches a certain level, cognitive function becomes evidently declined to be diagnosed dementia. Recent amyloid and tau imaging analyses have revealed that it is more than 20 years from senile plaque formation to the onset of dementia in Alzheimer’s disease.

These observations imply that removing Aβ after disease onset is too late because considerable amounts of neurons are already dead when the patients are diagnosed as having dementia. Thus, early detection of Aβ/tau pathology and prophylactic anti-oligomer treatment before neurons die are particularly important for dementia control and healthy aging. Rifampicin is a good candidate for such an anti-oligomer medicine. Rifampicin inhibits the formation of Aβ and tau oligomers; attenuates oxidative stress as a radical scavenger; and suppresses glial inflammation (Fig. 2). Our ML1808, a rifampicin-based collunarium, provides a promising measure for the prevention of neurodegenerative dementia.

Fig. 1. Pathological cascades of Alzheimer’s disease and frontotemporal dementia with tau.
Fig. 2. Anti-oligomer actions of rifampicin in neurodegenerative dementia.

Fig. 1. Pathological cascades of Alzheimer’s disease and frontotemporal dementia with tau.


Fig. 2. Anti-oligomer actions of rifampicin in neurodegenerative dementia.



しかし今では、毒性を示すのは線維形成前にできる可溶性の小さなオリゴマー(タンパク質が数個~数十個集まったもの)であり、これが神経細胞の機能を障害することで認知症が発症すると考えられています。 若いうちはオリゴマーができても細胞がこれを分解・除去しますが、歳を取って代謝機能が衰えてくるとオリゴマーが脳に溜まり始めます。