A novel detection method of cleaved plasma high‐molecular‐weight kininogen reveals its correlation with Alzheimer's pathology and cognitive impairment

Abstract

Introduction Accumulation of β-amyloid is a pathological hallmark of Alzheimer's disease (AD). β-Amyloid activates the plasma contact system leading to kallikrein-mediated cleavage of intact high-molecular-weight kininogen (HKi) to cleaved high-molecular-weight kininogen (HKc). Increased HKi cleavage is observed in plasma of AD patients and mouse models by Western blot. For potential diagnostic purposes, a more quantitative method that can measure HKc levels in plasma with high sensitivity and specificity is needed. Methods HKi/c, HKi, and HKc monoclonal antibodies were screened from hybridomas using direct ELISA with a fluorescent substrate. Results We generated monoclonal antibodies recognizing HKi or HKc specifically and developed sandwich ELISAs that can quantitatively detect HKi and HKc levels in human. These new assays show that decreased HKi and increased HKc levels in AD plasma correlate with dementia and neuritic plaque scores. Discussion High levels of plasma HKc could be used as an innovative biomarker for AD.

The Potential Emergence of Disease-Modifying Treatments for Alzheimer Disease: The Role of Primary Care in Managing the Patient Journey

“…65,[67][68][69][70][71]73 While there have been technological challenges to developing these tests, recent studies demonstrated promising results and suggest that they will be available for routine clinical use in the future, possibly in combination with each other or some of the other biomarkers in development. [57][58][59][60][61][62] Our calculations underscore that a combination of cognitive testing and plasma biomarkers is probably necessary for efficient testing for MCI due to AD in primary care settings. Both the MMSE and the MoCA when used alone would result in 4 to 5 false positives for every 1 true-positive case.…”

“…Several plasma biomarkers that are specific to the AD pathology, such as A␤ and tau, or indicative of nonspecific neuronal injury, such as neurofilament light chain are in development, and others are being explored. [57][58][59][60][61][62] Similar to CSF biomarkers, 8 plasma biomarkers may be most useful when used in combination.…”

High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease

“…Therefore, we determined levels of cHK in the plasma samples of sickle patients and healthy controls by ELISA as previously described. 29 We found that the levels of cHK were significantly increased in sickle cell patient samples ( Figure 1A), whereas levels of total intact HK (iHK) were not different between the two groups ( Figure 1B). Moreover, the ratio of cHK/iHK was also elevated in SCD patient plasma ( Figure 1C).…”

Cerebrospinal Fluid Levels of Kininogen‐1 Indicate Early Cognitive Impairment in Parkinson's Disease

“…15 A recently developed detection method of cleaved plasma KNG1 has been tested and further supported the theory that decreased levels of intact KNG1 and increased levels of cleaved KNG1 in AD plasma are associated with dementia and neuritic plaque scores, and may be used as novel AD markers. 16 Finally, an antibody against highmolecular-weight kininogen has been developed and shown to block beta-amyloid-induced bradykinin release in human plasma, suggesting new treatment strategies against bradykinin-driven pathologies. 17 In our study, higher CSF levels of KNG1 (not distinguishing between intact and cleaved) were found in patients with low RBANS score.…”