Frizzled-1 is involved in the neuroprotective effect of Wnt3a against aβ oligomers

被引:79
作者
Chacon, Marcelo A. [1 ]
Varela-Nallar, Lorena [1 ]
Inestrosa, Nibaldo C. [1 ]
机构
[1] Pontificia Univ Catolica Chile, Fac Ciencias Biol, Inst Milenio MIFAB, Ctr Regulac Celular & Patol Joaquin V Luco, Santiago, Chile
关键词
D O I
10.1002/jcp.21497
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The activation of the canonical Writ signaling pathway protects hippocampal neurons against the toxicity of Alzheimer's amyloid-beta-peptide (A beta), however, the role played by the Writ receptors Frizzleds, has not been studied. We report here that Frizzled-1 mediates the activation of the canonical Wnt/beta-catenin pathway by Wnt3a in PC 12 cells. In addition, the protective effect of Wnt3a against the toxicity of A beta oligomers was modulated by Frizzled-1 expression levels in both PC 12 cells and hippocampal neurons. Over-expression of Frizzled-1 significantly increased cell survival induced by Wnt3a and diminished caspase-3 activation, while knocking-clown Frizzled-1 expression by antisense oligonucleotides decreased the Wnt3a protection. Over-expression of wild-type beta-catenin, but not a transcriptionally inactive mutated version, prevented the toxicity of A suggesting that the transcription of Writ target genes may be involved in these events. This was confirmed by co-transfecting both Frizzled-1 and the inactive form of beta-catenin, which does not elicited protection levels similar to those showed with endogenous beta-catenin. Our results indicate that Wnt3a protects from A beta-oligomers toxicity by activating the canonical Wnt signaling pathway through the Frizzled-1 receptor, suggesting a therapeutic potential for this signaling pathway in the treatment of Alzheimer's disease.
引用
收藏
页码:215 / 227
页数:13
相关论文
共 59 条
[1]   Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by β-catenin-dependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT [J].
Almeida, M ;
Han, L ;
Bellido, T ;
Manolagas, SC ;
Kousteni, S .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2005, 280 (50) :41342-41351
[2]   Wnt-3a overcomes β-amyloid toxicity in rat hippocampal neurons [J].
Alvarez, AR ;
Godoy, JA ;
Mullendorff, K ;
Olivares, GH ;
Bronfman, M ;
Inestrosa, NC .
EXPERIMENTAL CELL RESEARCH, 2004, 297 (01) :186-196
[3]   BETA-AMYLOID FIBRILS INDUCE TAU-PHOSPHORYLATION AND LOSS OF MICROTUBULE-BINDING [J].
BUSCIGLIO, J ;
LORENZO, A ;
YEH, J ;
YANKNER, BA .
NEURON, 1995, 14 (04) :879-888
[4]   MAP2 IS LOCALIZED TO THE DENDRITES OF HIPPOCAMPAL-NEURONS WHICH DEVELOP IN CULTURE [J].
CACERES, A ;
BANKER, G ;
STEWARD, O ;
BINDER, L ;
PAYNE, M .
DEVELOPMENTAL BRAIN RESEARCH, 1984, 13 (02) :314-318
[5]  
Calderón FH, 1999, J NEUROSCI RES, V56, P620
[6]   Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain [J].
Caricasole, A ;
Copani, A ;
Caraci, F ;
Aronica, E ;
Rozemuller, AJ ;
Caruso, A ;
Storto, M ;
Gaviraghi, G ;
Terstappen, GC ;
Nicoletti, F .
JOURNAL OF NEUROSCIENCE, 2004, 24 (26) :6021-6027
[7]   Functional characterization of WNT7A signaling in PC12 cells -: Interaction with a FZD5•LRP6 receptor complex and modulation by dickkopf proteins [J].
Caricasole, A ;
Ferraro, T ;
Iacovelli, L ;
Barletta, E ;
Caruso, A ;
Melchiorri, D ;
Terstappen, GC ;
Nicoletti, F .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2003, 278 (39) :37024-37031
[8]   Frizzled receptor dimerization is sufficient to activate the Wnt/β-catenin pathway [J].
Carron, C ;
Pascal, A ;
Djiane, A ;
Boucaut, JC ;
Shi, DL ;
Umbhauer, M .
JOURNAL OF CELL SCIENCE, 2003, 116 (12) :2541-2550
[9]   β-sheet breaker peptide prevents Aβ-induced spatial memory impairments with partial reduction of amyloid deposits [J].
Chacón, MA ;
Barría, MI ;
Soto, C ;
Inestrosa, NC .
MOLECULAR PSYCHIATRY, 2004, 9 (10) :953-961
[10]   Activity-dependent synaptic Wnt release regulates hippocampal long term potentiation [J].
Chen, JY ;
Park, CS ;
Tang, SJ .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2006, 281 (17) :11910-11916