Increased plasma bradykinin level is associated with cognitive impairment in Alzheimer's patients

NEUROBIOLOGY OF DISEASE

卷:139

Article

Singh, Pradeep K.¹  Chen, Zu-Lin¹  Ghosh, Dhiman²  Strickland, Sidney¹  Norris, Erin H.¹ 

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

[2] Swiss Fed Inst Technol, Lab Phys Chem, WolfgangPauli Str 10, CH-8093 Zurich, Switzerland

关键词: Beta-amyloid;    Alzheimer's disease;    Contact activation system;    Inflammation;    Bradykinin;    High molecular weight kininogen;    Cognitive impairment;   

DOI  :  10.1016/j.nbd.2020.104833

来源: Elsevier

【 摘 要 】

Alzheimer's disease (AD) is characterized by the presence of proteinaceous brain deposits, brain atrophy, vascular dysfunction, and chronic inflammation. Along with cerebral inflammation, peripheral inflammation is also evident in many AD patients. Bradykinin, a proinflammatory plasma peptide, is also linked to AD pathology. For example, bradykinin infusion into the hippocampus causes learning and memory deficits in rats, and blockade of the bradykinin receptor lessens cognitive impairment in AD mouse models. Even though it has been hypothesized that plasma bradykinin could contribute to inflammation in AD, the level of plasma bradykinin and its association with beta-amyloid (A beta) pathology in AD patients had not been explored. Here, we assessed plasma bradykinin levels in AD patients and age-matched non-demented (ND) control individuals. We found significantly elevated plasma bradykinin levels in AD patients compared to ND subjects. Additionally, changes in plasma bradykinin levels were more profound in many AD patients with severe cognitive impairment, suggesting that peripheral bradykinin could play a role in dementia most likely via inflammation. Bradykinin levels in the cerebrospinal fluid (CSF) were reduced in AD patients and exhibited an inverse correlation with the CSF A beta 40/A beta 42 ratio. We also report that bradykinin interacts with the fibrillar form of A beta and co-localizes with A beta plaques in the post-mortem human AD brain. These findings connect the peripheral inflammatory pathway to cerebral abnormalities and identify a novel mechanism of inflammatory pathology in AD.