Abstract
Cerebrovascular dysfunction modifies amyloid β (Aβ) pathologies in neurons, worsening Alzheimer’s disease (AD), and however, the detailed molecular mechanism is still mostly missing. To unrevealed the mechanism, we developed a new in-vitro tri-culture system, consisting of brain endothelial cells, brain pericytes, and cortical neurons. Through analyses with this culture system, we found that the dysfunction of the pericytes induced by amylospheroids (ASPD), an AD patient-derived Aβ oligomer, activates δ-secretase, one of the amyloidogenic proteases, in the neurons, and these findings were reported at the previous annual meeting. Although the activated δ-secretase has been reported to play a significant role in the onset and progression of AD, the mechanism underlying its activation remains unclear. Therefore, the binding target of ASPD in the pericytes was explored, and then, we found that the membrane Na+, K+-ATPase α3 (NKAα3) serves as a binding target of ASPD by the confocal three-dimensional (3D) imaging and its high-content analyzing. Consistent with the results of image analyses, Knockdown of NKAα3 in the pericytes using siRNA attenuated the activation of δ-secretase by ASPD. In summary, we here show that the pericyte dysfunction may contribute to the activation of δ-secretase in AD.
