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

Daria Zamolodchikov; Zu-Lin Chen; Brooke A Conti; Thomas Renné; Sidney Strickland

doi:10.1073/pnas.1423764112

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

Standard

Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma. / Zamolodchikov, Daria; Chen, Zu-Lin; Conti, Brooke A; Renné, Thomas; Strickland, Sidney.

In: P NATL ACAD SCI USA, Vol. 112, No. 13, 31.03.2015, p. 4068-73.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Zamolodchikov, D, Chen, Z-L, Conti, BA, Renné, T & Strickland, S 2015, 'Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma', P NATL ACAD SCI USA, vol. 112, no. 13, pp. 4068-73. https://doi.org/10.1073/pnas.1423764112

APA

Zamolodchikov, D., Chen, Z-L., Conti, B. A., Renné, T., & Strickland, S. (2015). Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma. P NATL ACAD SCI USA, 112(13), 4068-73. https://doi.org/10.1073/pnas.1423764112

Vancouver

Zamolodchikov D, Chen Z-L, Conti BA, Renné T, Strickland S. Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma. P NATL ACAD SCI USA. 2015 Mar 31;112(13):4068-73. https://doi.org/10.1073/pnas.1423764112

Bibtex

@article{4c920807e2674bc8afa6f0fbf8195e3f,

title = "Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma",

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.",

author = "Daria Zamolodchikov and Zu-Lin Chen and Conti, {Brooke A} and Thomas Renn{\'e} and Sidney Strickland",

year = "2015",

month = mar,

day = "31",

doi = "10.1073/pnas.1423764112",

language = "English",

volume = "112",

pages = "4068--73",

journal = "P NATL ACAD SCI USA",

issn = "0027-8424",

publisher = "National Academy of Sciences",

number = "13",

}

RIS

TY - JOUR

T1 - Activation of the factor XII-driven contact system in Alzheimer's disease patient and mouse model plasma

AU - Zamolodchikov, Daria

AU - Chen, Zu-Lin

AU - Conti, Brooke A

AU - Renné, Thomas

AU - Strickland, Sidney

PY - 2015/3/31

Y1 - 2015/3/31

N2 - 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.

AB - 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.

U2 - 10.1073/pnas.1423764112

DO - 10.1073/pnas.1423764112

M3 - SCORING: Journal article

C2 - 25775543

VL - 112

SP - 4068

EP - 4073

JO - P NATL ACAD SCI USA

JF - P NATL ACAD SCI USA

SN - 0027-8424

IS - 13

ER -