7-ketocholesterol enhances BACE1-amyloid precursor protein cleavage and amyloidogenic peptide generation targeted by natural molecules

Alzheimer’s disease is a degenerative disorder characterised by amyloid beta aggregates activated by the accumulation of lipid molecules and their derivatives. The current therapeutics needs more effectiveness and signifies an undesirable effect. Disease-altering natural molecules-based treatment that are still behind the subject of in-depth research. In this study, bornyl acetate (BA) and menthol (ME) the natural monoterpenes were investigated for their neuroprotective effects. We analysed the lipid accumulation, amyloid generation and progressive pathologies like free radical generation, acetylcholinesterase levels, calcium accumulation and mitochondrial integrity induced by 7-ketocholesterol in SH-SY5Y cells. Furthermore, mediators involved in the amyloidogenic, inflammatory and apoptotic pathway were studied. Our results showed that the cells induced with 7-ketocholesterol upon co-treatment with BA and ME notably reduced lipid accumulation and amyloid generation through TLR4 suppression as well as enhanced ABCA1 mediated clearance. Co-treatment with BA and ME concurrently regulated oxidative stress, acetylcholinesterase activity, mitochondrial damage and intracellular calcification altered by 7-ketocholesterol in SH-SY5Y cells. Moreover, 7-ketocholesterol treated cells shows elevated mRNA levels of misfolded protein markers, apoptotic mediator, which were significantly downregulated by BA and ME co-treated cells. In addition, the protein expression of amyloidogenic, proinflammatory as well as pro-apoptotic markers were decreased by BA and ME co-treatment with 7KCh-induced cells. Overall, BA and ME mediated inhibition of amyloidogenic activation and cell survival against 7-ketocholesterol induced inflammation. In brief our study unveiled an auspicious disease targeted multipotential compounds to prevent the onset and progression of AD.