Transcription factor EB activation and neuro-protection by ouabain in Alzheimer’s disease models

Abstract

The neurofibrillary tangles containing abnormal hyperphosphorylated tau protein correlates with the degree of dementia in Alzheimer's disease (AD). In addition, features of autophagosome accumulation and damage due to autophagy, a degradation process of toxic protein aggregation in the cytosol, are also found in AD brain. These features indicate that regulation of the autophagy-lysosome system could be a therapeutic strategy for AD. Activation of Transcription factor EB (TFEB), a master regulator of autophagy-lysosome system gene transcription, reduces the amount of tau in transgenic mice that overexpress amyloid precursor protein (APP mice). Here, to search for therapeutic compounds for AD, it conducted two kinds of screening to identify pharmacologically active compounds that increase 1) neuronal viability in okadaic acid-induced tau hyperphosphorylation-related neurodegeneration models and 2) the nuclear localization of TFEB in high-content screening. Ouabain, a cardiac glycoside, was discovered as a common-hit compound in both screenings. It also exhibited significant protective effects in tau transgenic fly and mouse models in vivo. Through inhibition of the mechanistic target of rapamycin (mTOR) pathway and activation of TFEB, ouabain enhances downstream autophagy–lysosomal gene expression and cellular restorative properties and reduces phosphorylated tau in vitro and in vivo. This study reports the effects of ouabain as a promising therapeutic to modulate autophagy through the activation of TFEB and reduce the accumulation of abnormal toxic tau.