Accumulation of high molecular weight kininogen in the brains of Alzheimer's disease patients may affect microglial function by altering phagocytosis and lysosomal cathepsin activity

Bradykinin is a proinflammatory factor that mediates angioedema and inflammation in many diseases. It is a key player in some types of hereditary angioedema and is involved in septic shock, traumatic injury, Alzheimer’s disease (AD), and stroke, among others. Activation of the plasma contact system leads to elevated levels of plasma kallikrein, which cleaves high molecular weight kininogen (HK) to release bradykinin. Drug development for bradykinin-meditated pathologies has focused on designing inhibitors to the enzymes that cleave HK (to prevent bradykinin release) or antagonists of endothelial bradykinin receptors (to prevent downstream bradykinin action). Here we show a strategy to block bradykinin generation by using an HK antibody that binds to HK, preventing its cleavage and subsequent bradykinin release. We show that this antibody blocks dextran sodium sulfate-induced HK cleavage and bradykinin production. Moreover, while the pathogenic AD peptide β-amyloid (Aβ)42 cleaves HK and induces a dramatic increase in bradykinin production, our HK antibody blocked these events from occurring. These results may provide strategies for developing treatments for bradykinin-driven pathologies.

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High-molecular-weight forms of somatostatin are reduced in Alzheimer's disease and Down's syndrome

Neuroscience Letters ◽

10.1016/0304-3940(86)90051-0 ◽

1986 ◽

Vol 63 (2) ◽

pp. 141-146 ◽

Cited By ~ 25

Author(s):

Adrian R. Pierotti ◽

Anthony J. Harmar ◽

James Simpson ◽

Celia M. Yates

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Weight ◽

High Molecular Weight ◽

Down's Syndrome ◽

Down’S Syndrome

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High molecular weight Alzheimer's disease amyloid peptide immunoreactivity in human serum and CSF is an immunoglobulin G

Biochemical and Biophysical Research Communications ◽

10.1016/0006-291x(87)91312-x ◽

1987 ◽

Vol 145 (1) ◽

pp. 241-248 ◽

Cited By ~ 21

Author(s):

William M. Pardridge ◽

Harry V. Vinters ◽

Bruce L. Miller ◽

Wallace W. Tourtellotte ◽

Jody B. Eisenberg ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Weight ◽

Human Serum ◽

High Molecular Weight ◽

Immunoglobulin G ◽

Amyloid Peptide

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Aβ levels in the jugular vein and high molecular weight Aβ oligomer levels in CSF can be used as biomarkers to indicate the anti-amyloid effect of IVIg for Alzheimer’s disease

PLoS ONE ◽

10.1371/journal.pone.0174630 ◽

2017 ◽

Vol 12 (4) ◽

pp. e0174630 ◽

Cited By ~ 2

Author(s):

Takashi Kasai ◽

Masaki Kondo ◽

Ryotaro Ishii ◽

Akihiro Tanaka ◽

Suzuka Ataka ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Weight ◽

High Molecular Weight ◽

Jugular Vein ◽

Aβ Oligomer

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Detection of Soluble Amyloid-βOligomers and Insoluble High-Molecular-Weight Particles in CSF: Development of Methods with Potential for Diagnosis and Therapy Monitoring of Alzheimer's Disease

International Journal of Alzheimer s Disease ◽

10.4061/2011/151645 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 4

Author(s):

Susanne Aileen Funke

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Molecular Weight ◽

High Molecular Weight ◽

Therapy Monitoring ◽

Current Status ◽

Clinical Criteria ◽

Toxic Species ◽

Diagnosis And Therapy ◽

Preclinical Ad

The diagnosis of probable Alzheimer's disease (AD) can be established premortem based on clinical criteria like neuropsychological tests. Post mortem, specific neuropathological changes like amyloid plaques define AD. However, the standard criteria based on medical history and mental status examinations do not take into account the long preclinical features of the disease, and a biomarker for improved diagnosis of AD is urgently needed. In a large number of studies, amyloid-β(Aβ) monomer concentrations in CSF of AD patients are consistently and significantly reduced when compared to healthy controls. Therefore, monomeric Aβin CSF was suggested to be a helpful biomarker for the diagnosis of preclinical AD. However, not the monomeric form, but Aβoligomers have been shown to be the toxic species in AD pathology, and their quantification and characterization could facilitate AD diagnosis and therapy monitoring. Here, we review the current status of assay development to reliably and routinely detect Aβoligomers and high-molecular-weight particles in CSF.

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