Nibaldo C. Inestrosa

Investigation

We are interested in understanding the pathogenesis of Alzheimer's disease. We have proposed the hypothesis that the loss of Wnt signaling mediates amyloid neurotoxicity. There is now extensive evidence from our group and several laboratories abroad confirming this hypothesis. We showed that attenuation of Wnt/beta-catenin signaling abrogates Abeta neurotoxicity precisely in hippocampal neurons responsible for learning and memory. Tested conditions included the effects of lithium salts, Wnt ligands, protein kinase C activators, antioxidants, several neurotransmitter agonists as well as PPAR? agonists. Therefore, we are focused on defining Wnt cross-talk pathways and the relation between beta-amyloid toxicity and Wnt signaling, approaching the problem at cellular, molecular and organismic levels. We are incorporating APP trangenic mice as an in vivo system. A particular aim is to clarify the molecular mechanisms by which the Abeta peptide interferes with the Wnt signaling pathway. More important and because Alzheimer's disease entails synaptic failure, we are approaching in several experimental models the role of Wnt in synaptic structure and function.

Selected References

Author(s)	Title	Date
Quintanilla, RA., Muñoz, FJ., Metcalfe, MJ., Hitschfeld, M., Olivares, G., Godoy, JA., and Inestrosa, NC.	Trolox and 17 beta-estradiol protect against amyloid beta-peptide neurotoxicity by a mechanism that involves modulation of the wnt signaling pathway. J Biol. Chem 280: 11615-11625	0
Farias, G.G., Godoy, J.A., Hernandez, F., Avila, J., Fisher, A.. and Inestrosa, N.C	M1 muscarinic receptor activation protects neurons from ?-amyloid toxicity. A role for Wnt signaling pathway. Neurobiol Disease 17:337-348.(2004)	0
De Ferrari, G.V., Chacón, M.A. Barría, M.I., Garrido, J.L. Godoy, J.A. Olivares, G., Reyes, A. E., Alvarez, A., Bronfman, M. and Inestrosa, N.C.	Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by ?-amyloid fibrils Mol. Psychiatry 8: 195-208.(2003)	0
Opazo, C., Huang, X., Cherny, R.A., Moir, R.D., Roher,A.E., White, A.R., Cappai, R., Masters, C.L., Tanzi, R.E., Inestrosa, N.C. and Bush, A.	Metalloenzyme-like activity of Alzheimer´s disease ?-amyloid: Cu-dependent catalytic conversion of dopamine, cholesterol and biological reducing agents to neurotoxic H2O2. J Biol.	0
Inestrosa, N.C., Alvarez, A., Pérez, C., Moreno, R., Vicente, M., Linker, C., Soto, C. and Garrido, J.	Acetylcholinesterase accelerates assembly of amyloid-*-peptides into Alzheimer's amyloid fibrils: Possible role of the peripheral binding site of the enzyme. Neuron 16: 881-891.(1	0

Nibaldo C. Inestrosa

Academic CV

Investigation

Academic CV

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