Extending Lifespan of Alzheimer's Mode Nematode CL4176 Using a Novel Bifunctional Peptide with Inhibition ofβ-Amyloid Aggregation and Anti-oxidation

Alzheimer’s disease(AD)is a neurodegenerative disorder characterized by the deposition ofβ-amyloid peptide(Aβ)in the brain tissues,and an imbalance in the oxidant-antioxidant system.Compounds with antioxidant activity and the ability to inhibit Aβaggregation therefore potentially treat AD.In this study,we designed an iron-porphyrin containing bifunctional peptide(BP,Deuterohemin-AlaHisThrValGluLysLeuProPhePheAsp)based on natural microperoxidase-11(MP-11)and typicalβ-sheet breaker LPFFD(iAβ5p).This BP substantially reduced the aggregation of Aβand caused oligomer disassembly,by binding Aβwith affinity constant of 9.07μmol/L.Furthermore,it showed a neuroprotective effect on Aβ25—35 induced toxicity in SH-SY5Y cells,and significantly alleviated Aβ-induced paralysis and extended lifespan in Aβ1-42 transgenic C.elegans(CL4176).It also showed a potent peroxidase activity of 20.8 U/mg,and scavenged free radicals both in and in vivo.In addition,BP up-regulated the levels of hsp16.2,hsp16.41,and hsp12.6 mRNAs to 183.26%,160.16%,and 162.64%respectively,and down-regulated that of hsp70 to 36.76%in C.elegans.Taken together,the synthetic BP inhibited Aβaggregation and showed antioxidant activity,indicating the therapeutic potential of novel peptide drugs against AD.