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

**Yusuke Yakushiji 1,\*, Kazuhiro Kawamoto 1, Kazuyoshi Uchihashi 2, Masafumi Ihara 3, Shigehisa Aoki 2, Yukiko Nagaishi 1, Kohei Suzuyama 1, Yumiko Tsugitomi <sup>4</sup> and Hideo Hara <sup>1</sup>**


Received: 28 February 2020; Accepted: 24 March 2020; Published: 26 March 2020

**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
