AbstractLipooxygenase-5 (5-LOX), protein is involved in the pathologic phenotype of AD which includes amyloid-plague and tau hyperphosphorylation. This study aims to identify the mechanistic role in neuroprotection by peptide YWCS, the 5-LOX inhibitor in neurotoxic SH-SY5Y cell line developed by the treatment of Aβ25-35. The cells were treated with Aβ25-35 and with different doses of YWCS. The effect on cell survival pathways were determined by western blot using polyclonal anti body of p53, anti-Akt and anti-phosphorylated-Akt. Immunoprecipitation and mass spectroscopic studies were done to identify the altered proteins. Over expression of phosphorylated-Akt and 3 bands of p53 isoforms were observed which correspond to p73, Δ133p53 and Δ160p53 in the cells treated only with 80µM of YWCS compare to untreated cells. However, no alteration of total p53 and Akt were observed. The results exposed the novel mechanistic pathway of neuroprotection by 5-LOX inhibition, which is likely to be mediated by DNA DSB repair through p53 isoforms and PI3K/Akt pathway. Our finding has opened a new window in the therapeutic approach for the prevention of AD.