血管-神経の新規共培養系を用いたアルツハイマー病アミロイドβ凝集体“アミロスフェロイド”による血管内皮細胞障害を介した神経機能障害の解析：アンジオテンシンII遊離を介した神経BACE発現量の増加

抄録

In Alzheimer's disease (AD), the presence of cerebrovascular dysfunction worsens amyloid-beta (Aβ) pathology in neurons, but the molecular mechanism remains unclear. We have previously shown that Aβ assemblies, amylospheroids (ASPD) (Noguchi et al. JBC 2009), are present on blood vessels of AD brains and suppress the activity of endothelial NO synthase by binding to the α3 subunit of Na⁺ pump on vascular endothelial cells (Sasahara et al. iScience 2021). This suggested the possibility that ASPD-induced endothelial dysfunction may lead to worsening the Aβ pathology. To verify this, we newly constructed a tri-culture system using cerebrovascular endothelial cells, pericytes, and cerebral cortical neurons (reported at the last Annual Meeting). The addition of ASPD into the culture medium on the vascular cell side of the tri-culture system increased the expression of BACE protein in neurons. Interestingly, this increase was not observed in the system excluded pericytes. Preliminary data suggested that angiotensin II released from endothelial cells may play a role in the increase of BACE through the angiotensin AT2 receptor-bradykinin B2 receptor pathway in neurons. These findings suggest a new molecular mechanism between cerebrovascular dysfunction and the worsening of neuronal Aβ pathology.