Only recently, several evidences suggest that many abnormalities in vascular could be responsible for the Alzheimer’s Disease (AD). In particular, the reduced deformability of erythrocytes is one of the most suspected events associated to vascular abnormalities in AD. At this regard, it is known that NO is a regulatory factor of RBC mechanical properties, and recently it has been evidenced that amyloid beta peptide 1-42 (Abeta) inhibits endogenous erythrocyte nitric oxide synthase (eNOS) activity. However, the mechanism by which Abeta affects eNOS activity is not completely elucidated. In this study, we proposed to identify the intracellular pathways involved in Abeta-induced effects on eNOS activity. Protein kinase (PKC) is considered a prime candidate for eNOS pathway regulator, and phorbol-12 myristate- 13 acetate (PMA) and cheletryne chloride respectively a stimulator and inhibitor of PKC, were examined for their influence on erythrocyte eNOS activity and morphology. Our findings confirm previous data, suggesting a remodeling of the RBC membrane during Abeta exposure mediated by caspase 3. Our data also show Abeta-dependent changes in the membrane association of metabolic enzymes and signal transduction proteins. These results in particular define a dependence between eNOS, PKC and caspase 3 activities and Abeta mediated effects on erythrocyte morphology. These events could contribute to the vascular alterations associated with AD disease.
PKC-alfa AND CASPASE 3 ARE REQUIRED FOR AMYLOID BETA PEPTIDE MEDIATED IMPAIRMENT OF ENOS ACTIVITY IN HUMAN ERYTHROCYTES
MISITI, Francesco;
2013-01-01
Abstract
Only recently, several evidences suggest that many abnormalities in vascular could be responsible for the Alzheimer’s Disease (AD). In particular, the reduced deformability of erythrocytes is one of the most suspected events associated to vascular abnormalities in AD. At this regard, it is known that NO is a regulatory factor of RBC mechanical properties, and recently it has been evidenced that amyloid beta peptide 1-42 (Abeta) inhibits endogenous erythrocyte nitric oxide synthase (eNOS) activity. However, the mechanism by which Abeta affects eNOS activity is not completely elucidated. In this study, we proposed to identify the intracellular pathways involved in Abeta-induced effects on eNOS activity. Protein kinase (PKC) is considered a prime candidate for eNOS pathway regulator, and phorbol-12 myristate- 13 acetate (PMA) and cheletryne chloride respectively a stimulator and inhibitor of PKC, were examined for their influence on erythrocyte eNOS activity and morphology. Our findings confirm previous data, suggesting a remodeling of the RBC membrane during Abeta exposure mediated by caspase 3. Our data also show Abeta-dependent changes in the membrane association of metabolic enzymes and signal transduction proteins. These results in particular define a dependence between eNOS, PKC and caspase 3 activities and Abeta mediated effects on erythrocyte morphology. These events could contribute to the vascular alterations associated with AD disease.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
