Low-Dose Phosphodiesterase III Inhibitor Reduces the Vascular Amyloid Burden in Amyloid-β Protein Precursor Transgenic Mice

Abstract

A previous study reported that relatively high-dose cilostazol (0.3%) promoted the drainage of cerebrovascular amyloid-β (Aβ) protein in Aβ Precursor Protein (APP) transgenic mice overexpressing vasculotropic Aβ. We investigated whether lower-dose cilostazol can decrease micro-hemorrhages and Aβ deposition in the brain using APP transgenic mice. At baseline, 14-month-old female Tg2576 mice were randomly assigned to a control group (vehicle), aspirin group (0.01% aspirin), or cilostazol group (0.01% cilostazol). The severity of cerebral micro-hemorrhages (i.e., number), area of senile plaque, and severity of vascular amyloid burden (quantified with cerebral amyloid angiopathy (CAA) score (= number of Aβ-positive vessels × severity of amyloid burden of Aβ-positive vessels) were evaluated in the brain of mice aged 15 and 21−23 months. At 15 months, no differences were shown in each pathological change among the three groups. At 21−23 months, there were no differences in the severity of cerebral micro-hemorrhages or area of senile plaque among the three groups. However, the CAA score was significantly lower in the cilostazol compared to the control group (p=0.046, Mann−Whitney U test), although no difference was seen between the control and aspirin group. Our study showed that lower-dose cilostazol could reduce the vascular amyloid burden without increasing cerebral micro-hemorrhages in APP transgenic mice.

Keywords

• phosphodiesterase iii inhibitor
• cerebral micro-hemorrhage(s)
• cerebral amyloid angiopathy
• amyloid-β protein
• transgenic mice