| First Author | Bao XQ | Year | 2013 |
| Journal | PLoS One | Volume | 8 |
| Issue | 11 | Pages | e78033 |
| PubMed ID | 24223757 | Mgi Jnum | J:209326 |
| Mgi Id | MGI:5566964 | Doi | 10.1371/journal.pone.0078033 |
| Citation | Bao XQ, et al. (2013) FLZ alleviates the memory deficits in transgenic mouse model of Alzheimer's disease via decreasing beta-amyloid production and tau hyperphosphorylation. PLoS One 8(11):e78033 |
| abstractText | Alzheimer's disease (AD) is the most common cause of dementia worldwide and mainly characterized by the aggregated beta-amyloid (Abeta) and hyperphosphorylated tau. FLZ is a novel synthetic derivative of natural squamosamide and has been proved to improve memory deficits in dementia animal models. In this study, we aimed to investigate the mechanisms of FLZ's neuroprotective effect in APP/PS1 double transgenic mice and SH-SY5Y (APPwt/swe) cells. The results showed that treatment with FLZ significantly improved the memory deficits of APP/PS1 transgenic mice and decreased apoptosis of SH-SY5Y (APPwt/swe) cells. FLZ markedly attenuated Abeta accumulation and tau phosphorylation both in vivo and in vitro. Mechanistic study showed that FLZ interfered APP processing, i.e., FLZ decreased beta-amyloid precursor protein (APP) phosphorylation, APP-carboxy-terminal fragment (APP-CTF) production and beta-amyloid precursor protein cleaving enzyme 1 (BACE1) expression. These results indicated that FLZ reduced Abeta production through inhibiting amyloidogenic pathway. The mechanistic study about FLZ's inhibitory effect on tau phosphorylation revealed t the involvement of Akt/glycogen synthase kinase 3beta (GSK3beta) pathway. FLZ treatment increased Akt activity and inhibited GSK3beta activity both in vivo and in vitro. The inhibitory effect of FLZ on GSK3beta activity and tau phosphorylation was suppressed by inhibiting Akt activity, indicating that Akt/GSK3beta pathway might be the possible mechanism involved in the inhibitory effect of FLZ on tau hyperphosphorylation. These results suggested FLZ might be a potential anti-AD drug as it not only reduced Abeta production via inhibition amyloidogenic APP processing pathway, but also attenuated tau hyperphosphoylation mediated by Akt/GSK3beta. |
