Apolipoprotein E Polymorphism and Oxidative Stress in Peripheral Blood-Derived Macrophage-Mediated Amyloid-Beta Phagocytosis in Alzheimer's Disease Patients

摘要

Peripheral blood-derived macrophages isolated from Alzheimer's disease (AD) patients have earlier been reported to demonstrate ineffective phagocytosis of amyloid-beta compared to the age-matched control subjects. However, the mechanisms causing unsuccessful phagocytosis remain unclear. Oxidative stress and the presence of ApoE epsilon 4 allele has been reported to play a major role in the pathogenesis of AD, but the contribution of oxidative stress and ApoE epsilon 4 in macrophage dysfunction leading to ineffective A phagocytosis needs to be analyzed. A phagocytosis assay has been performed using FITC-labeled A and analyzed using flow cytometry and confocal imaging in patient samples and in THP-1 cells. Oxidative stress in patient-derived macrophages was analyzed by assessing the DNA damage using comet assay. ApoE polymorphism was analyzed using sequence-specific PCR and Hixson & Vernier Restriction isotyping protocol. In this study, we have analyzed the patterns of phagocytic inefficiency of macrophages in Indian population with a gradual decline in the phagocytic potential from mild cognitive impairment (MCI) to AD patients. Further, we have shown that the presence of ApoE epsilon 4 allele might also have a possible effect on the phagocytosis efficiency of the macrophages. Here, we demonstrate for the first time that oxidative stress could affect the amyloid-beta phagocytic potential of macrophages and hence by alleviating oxidative stress using curcumin, an anti-oxidant could enhance the amyloid-beta phagocytic efficacy of macrophages of patients with AD and MCI, although the responsiveness to curcumin might depends on the presence or absence of APOE epsilon 4 allele. Oxidative stress contributes significantly to decreased phagocytosis of A by macrophages. Moreover, the phagocytic inefficiency of macrophages was correlated to the presence of ApoE epsilon 4 allele. This study also found that the A-phagocytic potential of macrophage gets significantly enhanced in curcumin-treated patient-derived macrophages.