A possible mechanism for the enhanced toxicity of beta-amyloid protofibrils in Alzheimer's disease

被引：15

作者：

Chen, Zu-Lin ^{[1
]}

Singh, Pradeep K. ^{[1
]}

Calvano, Marissa ^{[1
]}

Norris, Erin H. ^{[1
]}

Strickland, Sidney ^{[1
]}

机构：

[1] Rockefeller Univ, Patricia & John Rosenwald Lab Neurobiol & Genet, New York, NY 10065 USA

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2023年 / 120卷 / 36期

关键词：

Alzheimer's; beta-amyloid; coagulation; MOLECULAR-WEIGHT KININOGEN; COGNITIVE IMPAIRMENT; CONTACT SYSTEM; ACTIVATION; BRAIN;

D O I：

10.1073/pnas.2309389120

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The amyloid-beta peptide (A beta) is a driver of Alzheimer's disease (AD). A beta monomers can aggregate and form larger soluble (oligomers/protofibrils) and insoluble ( fibrils) forms. There is evidence that A beta protofibrils are the most toxic form, but the reasons are not known. Consistent with a critical role for this form of A beta in AD, a recently FDA-approved therapeutic antibody targeted against protofibrils, lecanemab, slows the progression of AD in patients. The plasma contact system, which can promote coagulation and inflammation, has been implicated in AD pathogenesis. This system is activated by A beta which could lead to vascular and inflammatory pathologies associated with AD. We show here that the contact system is preferentially activated by protofibrils of A beta. A beta protofibrils bind to coagulation factor XII and high molecular weight kininogen and accelerate the activation of the system. Furthermore, lecanemab blocks A beta protofibril activation of the contact system. This work provides a possible mechanism for A beta protofibril toxicity in AD and why lecanemab is therapeutically effective.

引用

页数：3

共 17 条

[1] Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice [J].

Chen, Zu-Lin ;

Revenko, Alexey S. ;

Singh, Pradeep ;

MacLeod, A. Robert ;

Norris, Erin H. ;

Strickland, Sidney .

BLOOD, 2017, 129 (18) :2547-2556

[2] ARIA in patients treated with lecanemab (BAN2401) in a phase 2 study in early Alzheimer's disease [J].

Honig, Lawrence S. ;

Barakos, Jerome ;

Dhadda, Shobha ;

Kanekiyo, Michio ;

Reyderman, Larisa ;

Irizarry, Michael ;

Kramer, Lynn D. ;

Swanson, Chad J. ;

Sabbagh, Marwan .

ALZHEIMERS & DEMENTIA-TRANSLATIONAL RESEARCH & CLINICAL INTERVENTIONS, 2023, 9 (01)

[3] Early role of vascular dysregulation on late-onset Alzheimer's disease based on multifactorial data-driven analysis [J].

Iturria-Medina, Y. ;

Sotero, R. C. ;

Toussaint, P. J. ;

Mateos-Perez, J. M. ;

Evans, A. C. .

NATURE COMMUNICATIONS, 2016, 7

[4] Perspectives on future Alzheimer therapies: amyloid-β protofibrils - a new target for immunotherapy with BAN2401 in Alzheimer's disease [J].

Lannfelt, Lars ;

Moller, Christer ;

Basun, Hans ;

Osswald, Gunilla ;

Sehlin, Dag ;

Satlin, Andrew ;

Logovinsky, Veronika ;

Gellerfors, Par .

ALZHEIMERS RESEARCH & THERAPY, 2014, 6 (02)

[5] White Matter Hyperintensities Are a Core Feature of Alzheimer's Disease: Evidence from the Dominantly Inherited Alzheimer Network [J].

Lee, Seonjoo ;

Viqar, Fawad ;

Zimmerman, Molly E. ;

Narkhede, Atul ;

Tosto, Giuseppe ;

Benzinger, Tammie L. S. ;

Marcus, Daniel S. ;

Fagan, Anne M. ;

Goate, Alison ;

Fox, Nick C. ;

Cairns, Nigel J. ;

Holtzman, David M. ;

Buckles, Virginia ;

Ghetti, Bernardino ;

McDade, Eric ;

Martins, Ralph N. ;

Saykin, Andrew J. ;

Masters, Colin L. ;

Ringman, John M. ;

Ryan, Natalie S. ;

Forster, Stefan ;

Laske, Christoph ;

Schofield, Peter R. ;

Sperling, Reisa A. ;

Salloway, Stephen ;

Correia, Stephen ;

Jack, Clifford, Jr. ;

Weiner, Michael ;

Bateman, Randall J. ;

Morris, John C. ;

Mayeux, Richard ;

Brickman, Adam M. .

ANNALS OF NEUROLOGY, 2016, 79 (06) :929-939

[6] IDENTIFICATION OF PREKALLIKREIN AND HIGH-MOLECULAR-WEIGHT KININOGEN AS A COMPLEX IN HUMAN-PLASMA [J].

MANDLE, RJ ;

COLMAN, RW ;

KAPLAN, AP .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1976, 73 (11) :4179-4183

[7] The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Aβ protofibril formation [J].

Nilsberth, C ;

Westlind-Danielsson, A ;

Eckman, CB ;

Condron, MM ;

Axelman, K ;

Forsell, C ;

Stenh, C ;

Luthman, J ;

Teplow, DB ;

Younkin, SG ;

Näslund, J ;

Lannfelt, L .

NATURE NEUROSCIENCE, 2001, 4 (09) :887-893

[8]

Renne T., 2013, Hemostasis and Thrombosis: Basic Principles and Clinical Practice, P242

[9] Increased Contact System Activation in Mild Cognitive Impairment Patients with Impaired Short-Term Memory [J].

Singh, Pradeep K. ;

Chen, Zu-Lin ;

Strickland, Sidney ;

Norris, Erin H. .

JOURNAL OF ALZHEIMERS DISEASE, 2020, 77 (01) :59-65

[10] Increased plasma bradykinin level is associated with cognitive impairment in Alzheimer's patients [J].

Singh, Pradeep K. ;

Chen, Zu-Lin ;

Ghosh, Dhiman ;

Strickland, Sidney ;

Norris, Erin H. .

NEUROBIOLOGY OF DISEASE, 2020, 139

← 1 2 →