7,8-Dihydroxyflavone Ameliorates Cognitive Impairment by Inhibiting Expression of Tau Pathology in ApoE-Knockout Mice

Yang Tan,Xue B Cao,Yuzhen Li,Jiewen Chu,Hailong Guo,Shuke Nie,Xingjun Jiang,Yunjian Zhang,Fang Liu,Wende Zhu

doi:10.3389/fnagi.2016.00287

Abstract

7,8-Dihydroxyflavone (7,8-DHF), a tyrosine kinase B agonist that mimics the neuroprotective properties of brain-derived neurotrophic factor, which can not efficiently deliver into the brain, has been reported to be useful in ameliorating cognitive impairment in many diseases. Researches have indicated that apolipoprotein E-knockout (ApoE-KO) mouse was associated with cognitive alteration via various mechanisms. Our present study investigated the possible mechanisms of cognitive impairment of ApoE-KO mouse fed with western type diet and the protective effects of 7,8-DHF in improving spatial learning and memory in ApoE-KO mouse. Five-weeks-old ApoE-KO mice and C57BL/6 mice were chronically treated with 7,8-DHF (with a dosage of 5 mg/kg) or vehicles orally for 25 weeks, and then subjected to Morris water maze at the age of 30 weeks to evaluate the cognitive performances. Afterward, histology analysis and western blotting were performed. Spatial learning and memory deficits were observed in ApoE-KO mice, which were consistent with higher expression of active-asparaginyl endopeptidase (active-AEP) as well as AEP-derived truncated tau N368 compared with normal group. In addition to that, long-term treatment of 7,8-DHF dramatically ameliorated cognitive decline in ApoE-KO mice, accompanied by the activation in phosphorylated protein kinase B (Akt)/glycogen synthase kinase-3β (GSK-3β) pathway and down-regulated expression of tau S396 and PHF-tau (phosphorylated tau at ser396 and ser404 epitope). These findings suggested that cognitive impairment of ApoE-KO mouse might associate with tau pathology and 7,8-DHF could activate AKT and then phosphorylate its downstream molecule to inhibit expression of abnormal tau, meanwhile, 7,8-DHF could reduce the expression of active-AEP and then inhibit production of truncated tau N368.

Highlights

Apolipoprotein E (ApoE) has been closely linked to ADassociated pathology, like neurofibrillary tangles and amyloid plaques
In order to determine the effects of 7,8-DHF on levels of tau pathology of cognitive impairment ApoE knockout (ApoE-KO) mice, we evaluated the alteration of abnormal tau by PHF1 antibody, which can recognize neurofibrillary lesions of brain with higher affinity for phosphorylation of tau at serine residues 396, and tau S396 antibody
We demonstrated that memorydeteriorating of 30-weeks old ApoE-KO mice with western type diet might be associated with higher expression of truncated tau N368 as well as active-asparagine endopeptidase (AEP) in both brain cortex and hippocampus compared with C57BL/6 mice at the same age, whereas, the phosphorylated tau S396 might not play a vital role in impairing cognitive function

Summary

INTRODUCTION

Apolipoprotein E (ApoE) has been closely linked to ADassociated pathology, like neurofibrillary tangles and amyloid plaques. As a consequence of activating TrkB, 7,8-DHF inhibits obesity in female mice (Chan et al, 2015), reduces spine morphology abnormalities in fragile X syndrome (Tian et al, 2015), enhances axon regeneration and muscle renovation after peripheral nerves injuries (English et al, 2013), improves motor function and prolongs survival in Huntington’s disease (Jiang et al, 2013). It can reverse synapse loss and prevent memory deficits in Alzheimer’s disease (AD; Zhang et al, 2014a; Gao et al, 2016). We hypothesized that, comparing with C57BL/6 mouse, ApoE-KO mouse, with severe cerebrovascular atherosclerosis, expressed more tau pathology, which could aggravate cognitive impairment

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