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  • Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma.

Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma.

Proceedings of the National Academy of Sciences of the United States of America (2015-03-17)
Daria Zamolodchikov, Zu-Lin Chen, Brooke A Conti, Thomas Renné, Sidney Strickland
ABSTRACT

Alzheimer's disease (AD) is characterized by accumulation of the β-amyloid peptide (Aβ), which likely contributes to disease via multiple mechanisms. Increasing evidence implicates inflammation in AD, the origins of which are not completely understood. We investigated whether circulating Aβ could initiate inflammation in AD via the plasma contact activation system. This proteolytic cascade is triggered by the activation of the plasma protein factor XII (FXII) and leads to kallikrein-mediated cleavage of high molecular-weight kininogen (HK) and release of proinflammatory bradykinin. Aβ has been shown to promote FXII-dependent cleavage of HK in vitro. In addition, increased cleavage of HK has been found in the cerebrospinal fluid of patients with AD. Here, we show increased activation of FXII, kallikrein activity, and HK cleavage in AD patient plasma. Increased contact system activation is also observed in AD mouse model plasma and in plasma from wild-type mice i.v. injected with Aβ42. Our results demonstrate that Aβ42-mediated contact system activation can occur in the AD circulation and suggest new pathogenic mechanisms, diagnostic tests, and therapies for AD.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Bicinchoninic acid disodium salt hydrate, ≥98% (HPLC)
Sigma-Aldrich
Tantalum(V) ethoxide, 99.98% trace metals basis
Tantalum(V) ethoxide, packaged for use in deposition systems