In vitro study on amyloid beta aand#946; peptide induced innate immune responses and neuroprotection by ferulic acid

Abstract

Alzheimer s disease (AD) is a multifactorial neurodegenerative disorder associated with newlinethe amyloid beta (Aand#946;) and tau hallmarks. Neuroinflammation is now being considered as newlineone of the major causes and may have role in initiating AD pathology. Thus, in this study, newlinethe differentiated THP1 cells (macrophages), U-87 MG cells (astrocytes) were treated with newline(i) natural dietary phytochemical ferulic acid (FA), (ii) Aand#946;(25-35) and (iii) pre-treated with newlineFA followed by Aand#946; stress induction to evaluate the phenotype of macrophages in vitro. newlineFurther, to evaluate the changes in neuron physiology (differentiated SH-SY5Y cells) alone newlineas well as in co-culture with the macrophages/ astrocytes, cells were treated with FA newlineand/or Aand#946;. We observed that Aand#946; induced M1 phenotype in macrophages and A1 newlinephenotype in astrocytes, increased oxidative stress and induced expression of truncated newlineform of multifunctional enzyme, APE1 in macrophages. FA pretreatment along with Aand#946; newlinetreatment induced M2/A2 phenotype and also rescued macrophages/astrocytes and newlineneurons from the oxidative and inflammatory insult. However, neurons co-cultured with newlinemacrophages and treated with Aand#946; displayed pronounced increase in oxidative stress newlinemarkers, truncated N-terminal form (34 kDa) of APE1 expression, caspase 9 expression newlineand apoptosis inducing factor s (AIF) s translocation and co-localization with the newlinemultifunctional enzyme APE1 in the nucleus as compared to differentiated neurons alone. newlineAIF-APE1 interaction was confirmed in the nucleus and mitochondria via Co-IP, pointing newlineout that APE1 s truncated form may have a role in apoptosis via its interaction with AIF. newlineFurther, evaluation of metabolome associated changes in neurons alone as well as co- newlineiv newlinecultured with U-87 MG cells showed higher enrichment of pentose phosphate pathway newline(PPP) upon FA treatment, whereas Aand#946; treated neurons showed higher enrichment of newlineglycolysis/Warburg effect in both differentiated neurons as well as co-cultured neurons. Furthermore, evaluation of concentration of metabo