Protective effect of the phosphodiesterase III inhibitor cilostazol on amyloid beta-induced cognitive deficits associated with decreased amyloid beta accumulation

作者：Park Sun Haeng; Kim Ji Hyun; Bae Sun Sik; Hong Ki Whan; Lee Dong Seok; Leem Jae Yoon; Choi Byung Tae; Shin Hwa Kyoung^*

来源：Biochemical and Biophysical Research Communications, 2011, 408(4): 602-608.

DOI：10.1016/j.bbrc.2011.04.068

• Alzheimer's disease
• Amyloid beta
• Phosphorylated tau
• ApoE
• Microglia

Alzheimer's disease (AD), which is characterized by progressive cognitive impairment, is the most common neurodegenerative disease. Here, we investigated the preventive effect of a phosphodiesterase Ill inhibitor, cilostazol against cognitive decline in AD mouse model. In vitro studies using N2a cells stably expressing human amyloid precursor protein Swedish mutation (N2aSwe) showed that cilostazol decreased the amyloid beta (A beta) levels in the conditioned medium and cell lysates. Cilostazol attenuated the expression of ApoE, which is responsible for A beta aggregation, in N2aSwe. Intracerebroventricular injection of A beta(25-35) in C57BL/6J mice resulted in increased immunoreactivity of A beta and p-Tau, and microglia activation in the brain. Oral administration of cilostazol for 2 weeks before A beta administration and once a day for 4 weeks post-surgery almost completely prevented the A beta-induced increases of A beta and p-Tau immunoreactivity, as well as CD11b immunoreactivity. However, post-treatment with cilostazol 4 weeks after A beta administration, when A beta was already accumulated, did not prevent the A beta-induced neuropathological responses. Furthermore, cilostazol did not affect the neprilysin and insulin degrading enzymes involved in the degradation of the A beta peptide, but decreased ApoE levels in A beta-injected brain. In addition, cilostazol significantly improved spatial learning and memory in A beta-injected mice. The findings suggest that a phosphodiesterase III inhibitor, cilostazol significantly decreased A beta accumulation and improved memory impairment induced by A beta(25-35). The beneficial effects of cilostazol might be explained by the reduction of A beta accumulation and tau phosphorylation, not through an increase in A beta degradation but via a significant decrease in ApoE-mediated A beta aggregation. Cilostazol may be the basis of a novel strategy for the therapy of AD.

• 出版日期2011-5-20