Khan TK and Alkon DL (2006) An internally controlled peripheral biomarker for Alzheimer's disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin. Proc Natl Acad Sci USA 103: 13203–13207

Inflammatory signaling pathways mediated by protein kinase C (PKC) have been suggested to be involved in the pathogenesis of Alzheimer's disease (AD). PKC-mediated Erk1 and Erk2 phosphorylation has also been implicated by Alkon and colleagues in the storage of memory, deficits of which often occur at onset of AD. Khan and Alkon, therefore, investigated Erk1 and Erk2 phosphorylation in fibroblast cell lines from patients with AD in response to bradykinin, an activator of PKC pathways. They found that bradykinin-induced Erk1 and Erk2 phosphorylation differed between AD and control fibroblasts, providing a molecular biomarker for AD.

The level of intrinsic Erk1 and Erk2 phosphorylation was higher in control than in AD fibroblasts, suggesting that Erk signaling pathways are dysfunctional in AD. Stimulation with bradykinin caused an increase in Erk1 and Erk2 phosphorylation levels in AD fibroblasts, but not in control cells. An index derived from the change in the phosphorylated Erk1:Erk2 ratio produced by bradykinin stimulation accurately distinguished AD cell lines (n = 31) from age-matched controls and non-Alzheimer's dementia patients. In cases in which the diagnosis of AD had been confirmed by autopsy (n = 23), the index was 100% specific and 100% sensitive in distinguishing AD from both controls and non-Alzheimer's dementia. Of 20 cases in which clinical diagnosis of AD was in agreement with the index, 19 were confirmed by autopsy. There was an inverse correlation between index values and disease duration.

The authors conclude that the Erk1/Erk2 index could be an important aid to the accurate diagnosis of AD, particularly in the early stages of the disease when diagnosis is more uncertain.