Unconjugated
In brain, excess zinc alters the metabolism of amyloid precursor protein, leading to β-amyloid protein deposition, one of the hallmarks of Alzheimer's disease (AD) pathology. Recently, it has been reported that zinc accelerates in vitro tau fibrillization, another hallmark of AD. In the current study, we examined the effect of high-concentration zinc on tau phosphorylation in human neuroblastoma SH-SY5Y cells. We found that incubation of cells with zinc resulted in abnormal tau phosphorylation at Ser262/356. Moreover, the current study has investigated whether luteolin (Lu), a bioflavonoid, could decrease zinc-induced tau hyperphosphorylation and its underlying mechanisms. Using Western blot and protein phosphatase activity assay, activities of tau kinases and phosphatase were investigated. Our data suggest (1) that zinc induces tau hyperphosphorylation at Ser262/356 epitope and (2) that Lu efficiently attenuates zinc-induced tau hyperphosphorylation through not only its antioxidant action but also its regulation of the phosphorylation/dephosphorylation system.
BACKGROUND:
Alzheimer's disease (AD) is one of the most common dementia, which is not effectively cured to date. Amyloid-beta (Abeta) deposition cascade and disintegrity of brain extracellular matrix (ECM) scaffold attribute to the progress of AD. Thus, it maybe an effective way to treat AD by altering the processing of amyloid precursor protein (APP) and regaining the integrity of ECM. The peptide amphiphile (PA) with a laminin epitope isoleucine-lysine-valine-alanine-valine (IKVAV) (IKVAV-PA) can be trigged into ECM in vivo. In addition, IKVAV-PA could significantly improve cognitive impairment with remarkable increase of endoneurogensis in the hippocampus, as well as reduction of burden of amyloid plaque in the brain.
METHODS:
We used heterozygous AbetaPPswe/PS1dE9 double transgenic mice as the animal model of AD. After 1 week of initial stereotaxic administration into bilateral hippocampus, the mice were subjected to the Morris Water Maze (MWM) test. At the end of MWM test, immunohistochemical staining, Western blot and real-time polymerase chain reaction (PCR) were performed in mice.
RESULTS:
Here we showed that IKVAV-PA significantly improved cognitive impairment accompanying with reducing the burden of Abeta plaques, as well as the levels of soluble Abeta1-40 and Abeta1-42 in the cortex and hippocampus after 2 weeks of initial administration into bilateral hippocampus. Further examination demonstrated that IKVAV-PA also altered the processing of APP via inhibiting the gene expression of beta-secretase (BACE1), as well as improving the gene expression of insulin-degrading enzyme (IDE) and neprilysin (NEP).
CONCLUSION:
Our data suggest that IKVAV-PA may serve as an alternative therapeutic intervention for treating the learning and memory losses in AD.