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

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.

Aerobic exercise and a BDNF-mimetic therapy rescue learning and memory in a mouse model of Down syndrome

“…However, our results are consistent with at least one report showing increased TrkB phosphorylation only after chronic, but not acute DHF treatment in the hippocampus of the Tg2576 mouse model of Alzheimer’s disease 92 . In keeping with this and other reports 87 , 90 – 95 , we found that chronic DHF treatment increased TrkB phosphorylation in the hippocampus of Ts65Dn mice. However, we could not find a statistically significant increase in TrkB phosphorylation in the hippocampus of their WT littermates.…”

“…5A,B ). Nonetheless, other studies have reported activation of TrkB after chronic DHF treatment 87 , 90 – 95 . Accordingly, we found that chronic (4 weeks) administration of DHF significantly increased the level of P-TrkB Tyr817 (+26%) in the hippocampus of Ts65Dn mice (Fig.…”

Actions of Brain-Derived Neurotrophin Factor in the Neurogenesis and Neuronal Function, and Its Involvement in the Pathophysiology of Brain Diseases

“…Elliott et al reported that BDNF induced a dephosphorylation of tau in P19 mouse embryonic carcinoma cells within 15 min via PI3K signaling pathway [ 125 ]. 7,8-DHF was also reported to inhibit expression of abnormal tau via activating PI3K/Akt pathway [ 126 ]. MiR-322, the rodent homologue of human miR-424, is predicted to target the 3’-untranslated region (3’-UTR) of BDNF mRNA and found to be increased in AD mouse brain.…”

Bilateral Implantation of Shear Stress Modifier in ApoE Knockout Mouse Induces Cognitive Impairment and Tau Abnormalities

“…Second, BSSM implantation drastically accelerates the cognitive decline. In our previous study, ApoE -KO mice fed western type diet functioned normally in the behavioral test until 30 weeks old (Tan et al, 2016 ). Similarly, both spatial working memory and spatial reference memory were impaired in BCAS model only after long-term, i.e., 6 months of hypoperfusion (Nishio et al, 2010 ).…”