An internally controlled peripheral biomarker for Alzheimer’s disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin

doi:10.1073/pnas.0605411103

An internally controlled peripheral biomarker for Alzheimer’s disease: Erk1 and Erk2 responses to the inflammatory signal bradykinin

Tapan K. Khan* and
Daniel L. Alkon*,^†,^‡

*Blanchette Rockefeller Neurosciences Institute, Rockville, MD 20850; and
^†Department of Neurology, West Virginia University Medical School, Morgantown, WV 26506

Communicated by Bernhard Witkop, National Institutes of Health, Bethesda, MD, June 29, 2006 (received for review March 8, 2006)

Abstract

Cognitive impairment has recently been found to correlate with changes in peripheral inflammatory signals such as TNF-α and IL-1β. PKC isozymes regulate levels of TNF-α and IL-6 and the release of other cytokines and also show deficits in Alzheimer’s disease (AD) brains and skin fibroblasts. Here, we investigate MAPK Erk1 and Erk2 phosphorylation in response to the inflammatory agonist bradykinin, which activates PKC pathways. An internally controlled comparison of Erk1 and Erk2 produced an AD index that accurately distinguished fibroblasts of AD from those of normal controls and of non-AD dementias. This accuracy was demonstrated for Coriell Cell Repository (Coriell Institute of Medical Research, Camden, NJ) samples, as well as for samples analyzed on gels with autopsy diagnostic confirmation. AD Erk1 and Erk2 index values were inversely correlated with disease duration, suggesting maximal efficacy for early diagnosis. Finally, the results also demonstrate that, when the AD index agreed with the clinical diagnosis on the presence of AD, there was a high probability of accuracy based on autopsy validation. Thus, this peripheral molecular biomarker, based on differential Erk1 and Erk2 phosphorylation, could have important clinical utility for providing increased certainty in the positive diagnosis of AD, particularly in the early phase of disease progression.

Footnotes

^‡To whom correspondence should be addressed at:
Blanchette Rockefeller Neurosciences Institute, Academic and Research Building, 9601 Medical Center Drive, Rockville, MD 20850.
E-mail: dalkon{at}brni-jhu.org
Author contributions: T.K.K. and D.L.A. designed research; T.K.K. performed research; T.K.K. and D.L.A. analyzed data; and T.K.K. and D.L.A. wrote the paper.
Conflict of interest statement: No conflicts declared.
Abbreviations:

AD,

Alzheimer’s disease;

Aβ,

amyloid β;

APP,

amyloid precursor protein;

BK,

bradykinin;

P-Erk,

phosphorylated Erk.