Project goal
This project aims to study the functional dependence of Aβ phagocytosis in blood monocytes, isolated from AD patients, on the phenotype (M1/M2) and IDE concentration in these cells, and to study the possibility of pharmacological correction of Aβ proteolysis disturbance.
Project tasks:
Abstract: According to the amyloid hypothesis the progression of Alzheimer’s disease (AD) is driven by the disturbance of amyloid-β peptide (Аβ) metabolism and its accumulation in the brain. Clearance of Аβ from the brain and its further utilization in the blood is regulated via several pathways. The main mechanism of Аβ utilization in the central nervous system (CNS) is phagocytosis performed by brain microglia and blood-derived monocytes. According to the literature, 40%-60% of Аβ is utilized by peripheral blood monocytes and disturbance of this process can be a reason for Аβ accumulation in the brain. Monocytes represent a heterogeneous population of mononuclear cells with functionally different subpopulations of different phenotypes (M1 and M2). They are characterized by a certain degree of plasticity, and depending on age or pathological conditions, they can change their phenotypes. It is believed that the M2 phenotype has higher phagocytic activity, however, both phenotypes are involved in Аβ phagocytosis in AD patients. Nevertheless, the effectiveness of Aβ phagocytosis and its dependence on the monocytes’ phenotype in AD is still unknown. Several enzymes are responsible for the proteolysis of Аβ, however, therapeutically, the most interesting is the insulin-degrading enzyme (IDE). IDE is capable of cleaving Aβ oligomers into monomers and submolecular fragments. Dysfunction of IDE enzyme is observed in AD patients; however, mechanisms of pathogenesis are still poorly understood. Assessment of phagocytosis disturbance and its induction if AD patients are offered in the frame of this project.
This project aims to study the functional dependence of Aβ phagocytosis in blood monocytes, isolated from AD patients, on the phenotype (M1/M2) and IDE concentration in these cells, and to study the possibility of pharmacological correction of Aβ proteolysis disturbance.
Project tasks:
- Study of monocytes’ phenotype (M1/M2)
- Study of monocytes’ phagocytic activity in association with monocyte’s polarization phenotype (M1/M2)
- Study of somatostatin and tuftsin effects on IDE activity in blood monocytes in association with their phagocytic activity in vitro.
Abstract: According to the amyloid hypothesis the progression of Alzheimer’s disease (AD) is driven by the disturbance of amyloid-β peptide (Аβ) metabolism and its accumulation in the brain. Clearance of Аβ from the brain and its further utilization in the blood is regulated via several pathways. The main mechanism of Аβ utilization in the central nervous system (CNS) is phagocytosis performed by brain microglia and blood-derived monocytes. According to the literature, 40%-60% of Аβ is utilized by peripheral blood monocytes and disturbance of this process can be a reason for Аβ accumulation in the brain. Monocytes represent a heterogeneous population of mononuclear cells with functionally different subpopulations of different phenotypes (M1 and M2). They are characterized by a certain degree of plasticity, and depending on age or pathological conditions, they can change their phenotypes. It is believed that the M2 phenotype has higher phagocytic activity, however, both phenotypes are involved in Аβ phagocytosis in AD patients. Nevertheless, the effectiveness of Aβ phagocytosis and its dependence on the monocytes’ phenotype in AD is still unknown. Several enzymes are responsible for the proteolysis of Аβ, however, therapeutically, the most interesting is the insulin-degrading enzyme (IDE). IDE is capable of cleaving Aβ oligomers into monomers and submolecular fragments. Dysfunction of IDE enzyme is observed in AD patients; however, mechanisms of pathogenesis are still poorly understood. Assessment of phagocytosis disturbance and its induction if AD patients are offered in the frame of this project.