Development of apomorphine therapy for Alzheimer disease

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Alzheimer’s disease (AD) is the most frequent dementia in the elderly. However, the currently approved drugs’ effects on cognitive function are only slight, and novel drugs that improve memory function and inhibit neurodegeneration are being developed. We have found apomorphine (APO) to be a novel drug that targets amyloid-β42 (Aβ42) accumulating early in the neurons. In the present research theme, using cultured cells, AD mouse model (3xTg-AD) and brain tissues of AD patients, we have demonstrated1) that the majority of Aβ42 accumulating in the neurons is the Aβ42 oligomer with toxic turn formation;2) that accumulation of the toxic turn Aβ42 oligomer is associated wuth endoplasmic reticulum stress;3) that APO treatment promotes degradation of the toxic turn Aβ42 oligomer;4) APO treatment is more effective for the AD mouse model than lithium treatment which inhibits hyper-phosphrylation of tau protein;5) that Apokyn（R）, a drug of APO for Parkinson’s disease patients, is effective enough at low dose for memory function of the AD mouse model;6) that the anti-AD effects of APO is not simply due to stimulation of dopamine receptors;7) that APO elevates the activity of Insulin-degrading enzyme (IDE) in the cultured cells; and8) that one of the molecular mechanisms of APO effects may be inhibition of the insulin resistance leading to elevation of the IDE activity.In the future, we will study about elevation of the insulin resistance in the brains of the AD mouse model and effects of APO treatment on the insulin resistance, and develop new drugs for the brain diabetes in AD.