The identification of Wnt signaling as a major player in the regulation of adult hippocampal neurogenesis is probably one of the most important scientific discoveries of this year. Gage´s lab not only opens an exciting new avenue for the understanding of the environmental signals that influence adult neurogenesis, but also improves prospects for potential therapeutic benefits of stem cell technology in brain aging and Alzheimer disease.

For AD patients, we need a “pathway” that increases the neurogenic potential of adult brain cells and at the same time is able to protect neurons from the toxic effects of the amyloid-β peptide (Aβ). Previous studies from our lab indicate that activation of Wnt signaling prevents Aβ neurotoxicity in hippocampal neurons (De Ferrari et al., 2003; Quintanilla et al., 2005). That astrocyte-derived Wnts and Wnt/β-catenin signaling in adult hippocampal stem/progenitor cells (AHPs) are substantial contributors to the neuronal differentiation of AHPs induced by hippocampal astrocytes is very appealing for AD. A consistent feature around the amyloid...  Read more

The identification of Wnt signaling as a major player in the regulation of adult hippocampal neurogenesis is probably one of the most important scientific discoveries of this year. Gage´s lab not only opens an exciting new avenue for the understanding of the environmental signals that influence adult neurogenesis, but also improves prospects for potential therapeutic benefits of stem cell technology in brain aging and Alzheimer disease.

For AD patients, we need a “pathway” that increases the neurogenic potential of adult brain cells and at the same time is able to protect neurons from the toxic effects of the amyloid-β peptide (Aβ). Previous studies from our lab indicate that activation of Wnt signaling prevents Aβ neurotoxicity in hippocampal neurons (De Ferrari et al., 2003; Quintanilla et al., 2005). That astrocyte-derived Wnts and Wnt/β-catenin signaling in adult hippocampal stem/progenitor cells (AHPs) are substantial contributors to the neuronal differentiation of AHPs induced by hippocampal astrocytes is very appealing for AD. A consistent feature around the amyloid deposits is the appearance of reactive astrocytes, which may release cytokines. It is therefore possible that in AD patients, a controlled release of Wnt ligands or Wnt pathway activation (i.e., GSK-3β inhibitors) would eventually help to induce neuronal survival and cell fate instruction from stem/progenitor cells.

For our lab, it is rewarding that Wnt3 became the ligand involved in the regulation of adult hippocampal neurogenesis, because it was the same Wnt ligand that we found to prevent Aβ neurotoxicity in hippocampal neurons (Alvarez et al., 2004). Fred Gage´s study on the effect of the canonical Wnt pathway on adult neurogenesis offers an opportunity for AD researchers to be more aware of the potential implications of the relationship between Wnt signaling and AD.

References:
De Ferrari GV, Chacón MA, Barría MI, Garrido JL, Godoy JA, Olivares G, Reyes AE, Alvarez A, Bronfman M, Inestrosa NC. (2003) Activation of Wnt signaling rescues neurodegeneration and behavioral impairments induced by beta-amyloid fibrils. Molecular Psychiatry 8: 195-208. Abstract

Quintanilla RA, Munoz FJ, Metcalfe MJ, Hitschfeld M, Olivares G, Godoy JA, Inestrosa NC (2005) Trolox and 17beta-estradiol protect against amyloid beta-peptide neurotoxicity by a mechanism that involves modulation of the Wnt signaling pathway. J. Biol. Chem. 280:11615-11625. Abstract

Alvarez AR, Godoy JA, Mullendorff K, Olivares GH, Bronfman M, Inestrosa NC (2004) Wnt-3a overcomes beta-amyloid toxicity in rat hippocampal neurons. Exp Cell Res 297:186-196. Abstract

View all comments by Nibaldo Inestrosa

The canonical Wnt signaling pathway has multiple roles in stem/progenitor cells. In embryonic stem cells, activation of Wnt promotes self-renewal and inhibits neural differentiation (1,2). In the central nervous system, Wnt3a is required for neural progenitor proliferation and hippocampal development (3). Wnt family members are also necessary for expanding neural crest progenitors (4). In contrast, Wnt/β-catenin promotes cell fate specification rather than progenitor cell expansion in the dorsal spinal cord (5) and in the developing cortex (6). Thus, the role of Wnt in stem/progenitor cells seems to depend both on the context and cell-intrinsic properties.

Now, this paper provides a compelling piece of evidence about the role of Wnt signaling in the regulation of adult hippocampal neurogenesis. Part of the relevance of this finding relies on the fact that abnormalities of Wnt signaling are involved in brain diseases that might benefit from support of endogenous neurogenesis, such as cerebral ischemia (7) and Alzheimer disease (8,9).

Nibaldo Inestrosa and coworkers first...  Read more

The canonical Wnt signaling pathway has multiple roles in stem/progenitor cells. In embryonic stem cells, activation of Wnt promotes self-renewal and inhibits neural differentiation (1,2). In the central nervous system, Wnt3a is required for neural progenitor proliferation and hippocampal development (3). Wnt family members are also necessary for expanding neural crest progenitors (4). In contrast, Wnt/β-catenin promotes cell fate specification rather than progenitor cell expansion in the dorsal spinal cord (5) and in the developing cortex (6). Thus, the role of Wnt in stem/progenitor cells seems to depend both on the context and cell-intrinsic properties.

Now, this paper provides a compelling piece of evidence about the role of Wnt signaling in the regulation of adult hippocampal neurogenesis. Part of the relevance of this finding relies on the fact that abnormalities of Wnt signaling are involved in brain diseases that might benefit from support of endogenous neurogenesis, such as cerebral ischemia (7) and Alzheimer disease (8,9).

Nibaldo Inestrosa and coworkers first suggested that a loss of Wnt function is implicated in the pathophysiology of neuronal degeneration in AD (8). Accordingly, we have found that Dickkopf-1 (DKK-1), a negative modulator of the Wnt pathway, is induced in cultured neurons challenged with Aβ, as well as in degenerating neurons of AD brain (9). The induction of DKK-1 contributes to the pathological cascade activated by β-amyloid and particularly to tau hyperphosphorylation. We have suggested that DKK-1 antagonists or drugs that rescue the Wnt pathway acting downstream of the DKK-1 blockade are potential neuroprotective agents in AD. Based on Rusty Gage’s study, we can start thinking about the possibility that these drugs might also help to sustain neurogenesis in AD. However, we must consider that the feasibility of such a treatment could be influenced by a number of disease-related extracellular factors that may modify the response of progenitor cells to Wnt.

References:
1. Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH. Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med. 2004; 10(1): 55-63. Abstract

2. Aubert J, Dunstan H, Chambers I, Smith A. Functional gene screening in embryonic stem cells implicates Wnt antagonism in neural differentiation. Nat Biotechnol. 2002; 20(12): 1240-5. Abstract

3. Lee SM, Tole S, Grove E, McMahon AP. A local Wnt-3a signal is required for development of the mammalian hippocampus. Development. 2000; 127(3): 457-67. Abstract

4. Ikeya M, Lee SM, Johnson JE, McMahon AP, Takada S. Wnt signalling required for expansion of neural crest and CNS progenitors. Nature. 1997; 389(6654): 966-70. Abstract

5. Muroyama Y, Fujihara M, Ikeya M, Kondoh H, Takada S. Wnt signaling plays an essential role in neuronal specification of the dorsal spinal cord. Genes Dev. 2002; 16(5): 548-53. Abstract

6. Hirabayashi Y, Itoh Y, Tabata H, Nakajima K, Akiyama T, Masuyama N, Gotoh Y. The Wnt/β-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development. 2004; 131(12): 2791-801. Abstract

7. Cappuccio I, Calderone A, Busceti CL, Biagioni F, Pontarelli F, Bruno V, Storto M, Terstappen GT, Gaviraghi G, Fornai F, Battaglia G, Melchiorri D, Zukin S, Nicoletti F, Caricasole A. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is required for the development of ischemic neuronal death. J Neurosci. 2005; 25(10): 2647-57. Abstract

8. De Ferrari GV, Inestrosa NC. Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev. 2000; 33(1): 1-12. Abstract

9. Caricasole A, Copani A, Caraci F, Aronica E, Rozemuller AJ, Caruso A, Storto M, Gaviraghi G, Terstappen GC, Nicoletti F. Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci. 2004; 24(26): 6021-7. Abstract

View all comments by Agata Copani