Sun-Jung Cho

Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a component of the extracellular environment and is suggested to play an indirect role in regulating Aβ production and the pathophysiology of Aβ deposition in brains. However, studies on the amount of TIMP-3 in bodily fluids of Alzheimer’s disease (AD) patients have not been conducted. Here, we investigated the relationship between fluid TIMP-3 levels and AD pathology. We first showed that the fluid levels of TIMP-3 were lower in AD dementia patients compared with in non-AD patients. ELISA results revealed that plasma levels of TIMP-3 in 65 patients with AD were significantly lower than those in 115 healthy control subjects and 71 mild cognitive impairment (MCI) subjects. Furthermore, we found that cerebrospinal fluid (CSF) level of TIMP-3 was decreased in AD compared with that in healthy control. These data suggest that fluid TIMP-3 levels negatively correlated with progress of cognitive decline. Collectively, our study suggests that alterations of fluid TIMP-3 levels might be associated with AD pathology.

Alzheimer’s disease (AD) is characterized by amyloid plaques and pathologic cerebrovascular remodeling. Cerebrovascular abnormalities may contribute to the pathology of AD, but the molecular mechanisms are not fully understood. In this study, we evaluated blood–brain barrier (BBB) disruption and the role of VE-cadherin in the progression of amyloid pathology. Here, we determined that levels of VE-cadherin are decreased in brain vessels of AD patients and mouse model of AD. In vitro experiments showed that the disappearance of VE-cadherin by beta-amyloid at the endothelial cell surface was due to cleavage of VE-cadherin. VE-cadherin cleavage was inhibited by a γ-secretase and ADAM10 inhibitor. The disappearance of VE-cadherin in brain vessels was also seen in amyloid precursor protein transgenic mice. In the postmortem brain of individuals with AD, furthermore, levels of VE-cadherin were significantly reduced in vessels. Dementia patients showed a distinct blood biochemical profile characterized by high soluble VE-cadherin (sVEC). There was a strong association between plasma sVEC (adjusted odds ratio = 3.41, P < 0.001) and dementia. These results suggest that measurements of plasma VE-cadherin could have the potential for predicting the risk of progressive AD.