Dataset Information
Phosphodiesterase III inhibitor promotes drainage of cerebrovascular ?-amyloid.
Ontology highlight
ABSTRACT: Objective
Brain amyloidosis is a key feature of Alzheimer's disease (AD). It also incorporates cerebrovascular amyloid ? (A?) in the form of cerebral amyloid angiopathy (CAA) involving neurovascular dysfunction. We have recently shown by retrospective analysis that patients with mild cognitive impairment receiving a vasoactive drug cilostazol, a selective inhibitor of phosphodiesterase (PDE) III, exhibit significantly reduced cognitive decline. Here, we tested whether cilostazol protects against the disruption of the neurovascular unit and facilitates the arterial pulsation-driven perivascular drainage of A? in AD/CAA.Methods
We explored the expression of PDE III in postmortem human brain tissue followed by a series of experiments examining the effects of cilostazol on A? metabolism in transgenic mice (Tg-SwDI mice) as a model of cerebrovascular ?-amyloidosis, as well as cultured neurons.Results
We established that PDE III is abnormally upregulated in cerebral blood vessels of AD and CAA subjects and closely correlates with vascular amyloid burden. Furthermore, we demonstrated that cilostazol treatment maintained cerebral hyperemic and vasodilative responses to hypercapnia and acetylcholine, suppressed degeneration of pericytes and vascular smooth muscle cells, promoted perivascular drainage of soluble fluorescent A?1-40, and rescued cognitive deficits in Tg-SwDI mice. Although cilostazol decreased endogenous A? production in cultured neurons, C-terminal fragment of amyloid precursor protein expression was not altered in cilostazol-treated Tg-SwDI mice.Interpretation
The predominant action of cilostazol on A? metabolism is likely to facilitate A? clearance due to the sustained cerebrovascular function in vivo. Our findings mechanistically demonstrate that cilostazol is a promising therapeutic approach for AD and CAA.
SUBMITTER: Maki T
PROVIDER: S-EPMC4184555 | biostudies-literature | 2014 Aug
REPOSITORIES: biostudies-literature
Publications
Phosphodiesterase III inhibitor promotes drainage of cerebrovascular β-amyloid.
Annals of clinical and translational neurology 20140708 8
<h4>Objective</h4>Brain amyloidosis is a key feature of Alzheimer's disease (AD). It also incorporates cerebrovascular amyloid β (Aβ) in the form of cerebral amyloid angiopathy (CAA) involving neurovascular dysfunction. We have recently shown by retrospective analysis that patients with mild cognitive impairment receiving a vasoactive drug cilostazol, a selective inhibitor of phosphodiesterase (PDE) III, exhibit significantly reduced cognitive decline. Here, we tested whether cilostazol protects ...[more]
