endothelin-1 and Lewy-Body-Disease

In dementia with Lewy bodies (DLB), blood flow tends to be reduced in the occipital cortex. We previously showed elevated activity of the endothelin and angiotensin pathways in Alzheimer's disease (AD). We have measured endothelin-1 (ET-1) level and angiotensin-converting enzyme (ACE) activity in the occipital cortex in DLB and control brains. We also measured vascular endothelial growth factor (VEGF); factor VIII-related antigen (FVIIIRA) to indicate microvessel density; myelin-associated glycoprotein (MAG), a marker of ante-mortem hypoperfusion; total α-synuclein (α-syn) and α-synuclein phosphorylated at Ser129 (α-syn-p129). In contrast to findings in AD, ACE activity and ET-1 level were unchanged in DLB compared with controls. VEGF and FVIIIRA levels were, however, significantly lower in DLB. VEGF correlated positively with MAG concentration (in keeping with a relationship between reduction in VEGF and hypoperfusion), and negatively with α-syn and α-syn-p129 levels. Both α-syn and α-syn-p129 levels increased in human SH-SY5Y neuroblastoma cells after oxygen-glucose deprivation (OGD), and VEGF level was reduced in SH-SY5Y cells overexpressing α-syn. Taken together, our findings suggest that reduced microvessel density rather than vasoconstriction is responsible for lower occipital blood flow in DLB, and that the loss of microvessels may result from VEGF deficiency, possible secondary to the accumulation of α-syn.

Topics: Aged; Aged, 80 and over; alpha-Synuclein; Capillaries; Cell Hypoxia; Cell Line, Tumor; Endothelial Growth Factors; Endothelin-1; Female; Glucose; Humans; Lewy Body Disease; Male; Myelin-Associated Glycoprotein; Occipital Lobe; Peptidyl-Dipeptidase A; Phosphorylation; Vascular Endothelial Growth Factor A; von Willebrand Factor