Alzheimer's disease skin fibroblasts selectively express a bradykinin signaling pathway mediating tau protein Ser phosphorylation.
Increased Ser phosphorylation of tau microtubule-associated protein in the brain is an early feature of Alzheimer's disease (AD) that precedes progression of the disease to frank neuronal disruption. We demonstrate that bradykinin (BK) B2 receptor activation leads to selective Ser phosphorylation of tau in skin fibroblasts from persons who have or will develop AD due to Presenilin 1 mutations or Trisomy 21, but not in skin fibroblasts from normal individuals at any age. The increased signal transduction in AD fibroblasts that culminates in tau Ser phosphorylation reflects modification of the G protein-coupled BK B2 receptors themselves. Both the BK B2 receptor modification and BK-mediated tau Ser phosphorylation are dependent on activation of protein kinase C and can be detected in fibroblasts from persons with Trisomy 21 two decades before the characteristic onset of AD. This dysregulated signaling cascade in AD may thus be expressed throughout life as an aberrant pathway in peripheral tissues more accessible than brain for molecular analysis. The sites of greatest BK B2 receptor expression in brain overlap with those areas displaying the earliest pathology in the course of AD, suggesting that BK receptor pathway dysfunction may be a molecular signature yielding information about the pathogenesis of AD.
Jong
Yuh-Jiin I
YJ
Department of Anatomy and Neurobiology, Washington University School of Medicine, 660 S. Euclid Ave., Campus Box 8108, St. Louis, MO 63110, USA.
Ford
Stephanie R
SR
Seehra
Kuljeet
K
Malave
Victor Brian
VB
Baenziger
Nancy Lewis
NL
D000328:Adult; D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D001920:Bradykinin / Q000494:pharmacology; D002460:Cell Line; D004314:Down Syndrome / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008954:Models, Biological; D009154:Mutation; D010766:Phosphorylation; D053764:Presenilin-1; D011493:Protein Kinase C / Q000378:metabolism; D043782:Receptor, Bradykinin B2 / Q000378:metabolism*; D012694:Serine / Q000378:metabolism*; D015398:Signal Transduction; D012867:Skin / Q000166:cytology; D016875:tau Proteins / Q000737:chemistry / Q000378:metabolism*
D008565:Membrane Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D043782:Receptor, Bradykinin B2; D016875:tau Proteins; D012694:Serine; D011493:Protein Kinase C; D001920:Bradykinin