Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain.
We used primary cultures of cortical neurons to examine the relationship between beta-amyloid toxicity and hyperphosphorylation of the tau protein, the biochemical substrate for neurofibrillary tangles of Alzheimer's brain. Exposure of the cultures to beta-amyloid peptide (betaAP) induced the expression of the secreted glycoprotein Dickkopf-1 (DKK1). DKK1 negatively modulates the canonical Wnt signaling pathway, thus activating the tau-phosphorylating enzyme glycogen synthase kinase-3beta. DKK1 was induced at late times after betaAP exposure, and its expression was dependent on the tumor suppressing protein p53. The antisense induced knock-down of DKK1 attenuated neuronal apoptosis but nearly abolished the increase in tau phosphorylation in betaAP-treated neurons. DKK1 was also expressed by degenerating neurons in the brain from Alzheimer's patients, where it colocalized with neurofibrillary tangles and distrophic neurites. We conclude that induction of DKK1 contributes to the pathological cascade triggered by beta-amyloid and is critically involved in the process of tau phosphorylation.
Caricasole
Andrea
A
Siena Biotech, 53100 Siena, Italy.
Copani
Agata
A
Caraci
Filippo
F
Aronica
Eleonora
E
Rozemuller
Annemieke J
AJ
Caruso
Alessandra
A
Storto
Marianna
M
Gaviraghi
Giovanni
G
Terstappen
Georg C
GC
Nicoletti
Ferdinando
F
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D016291:Dizocilpine Maleate / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects; D018698:Glutamic Acid / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007124:Immunoenzyme Techniques; D036341:Intercellular Signaling Peptides and Proteins; D009410:Nerve Degeneration / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016874:Neurofibrillary Tangles / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011810:Quinoxalines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology; D051153:Wnt Proteins; D051028:bcl-2-Associated X Protein; D016875:tau Proteins / Q000378:metabolism
D016229:Amyloid beta-Peptides; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D011506:Proteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011810:Quinoxalines; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D051153:Wnt Proteins; C074636:amyloid beta-protein (25-35); D051028:bcl-2-Associated X Protein; D016875:tau Proteins; D018698:Glutamic Acid; C056723:FG 9041; D016291:Dizocilpine Maleate; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3