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...  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...  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

I very much look forward to hearing updates about the progress of the center. I hope they will be able to produce quantifiable data of improved outcomes - quality of life, lowered medical costs, delay in nursing home placements, etc.

View all comments by J. Lucy Boyd

In this paper, He and Shen report that the renewal capacity of glial progenitor cells (GPCs) isolated from the superior temporal cortex of Alzheimer disease (AD) patients is reduced compared to that of cells from healthy controls and that this reduced neurogenesis capacity correlates with an increased GSK-3β activity and an increased phosphorylation of β-catenin. They also found that treating GPCs from healthy controls with aggregates of Aβ led to increased β-catenin phosphorylation and reduced neurogenesis. These findings suggest that Aβ-induced interruption of Wnt signaling contributes to the impairment of neurogenesis in AD patients.

Early in 2000, we proposed that a loss of the Wnt signaling was triggered by Aβ in AD (2). Later on we, and others, confirmed that Aβ induces an impairment of Wnt signaling function, indicating that a sustained loss of this pathway occurs during Aβ neurodegeneration (3). The reduction in neurogenesis in GPCs is accompanied by a decrease in the Wnt signaling function (1). This is entirely consistent with...  Read more

In this paper, He and Shen report that the renewal capacity of glial progenitor cells (GPCs) isolated from the superior temporal cortex of Alzheimer disease (AD) patients is reduced compared to that of cells from healthy controls and that this reduced neurogenesis capacity correlates with an increased GSK-3β activity and an increased phosphorylation of β-catenin. They also found that treating GPCs from healthy controls with aggregates of Aβ led to increased β-catenin phosphorylation and reduced neurogenesis. These findings suggest that Aβ-induced interruption of Wnt signaling contributes to the impairment of neurogenesis in AD patients.

Early in 2000, we proposed that a loss of the Wnt signaling was triggered by Aβ in AD (2). Later on we, and others, confirmed that Aβ induces an impairment of Wnt signaling function, indicating that a sustained loss of this pathway occurs during Aβ neurodegeneration (3). The reduction in neurogenesis in GPCs is accompanied by a decrease in the Wnt signaling function (1). This is entirely consistent with our studies, which indicate that a reduction in Wnt signaling promotes the progression of AD.

Within the intact adult mammalian brain, active neurogenesis occurs in two discrete “neurogenic” regions: the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone of the lateral ventricles in the forebrain. With the work of He and Shen (1) on the cortex, it became clear that the Wnt signaling pathway is involved in the neurogenesis of the two neurogenic sites, since previous work (4) established the role of Wnt signaling in the neurogenesis of the adult mouse hippocampus.

He and Shen (1) treated GPCs from healthy individuals with aggregates of Aβ and found an increase in β-catenin phosphorylation and a reduced neurogenesis. Considering that Aβ oligomers are the toxic entities in AD, it would be nice to see whether incubation of GPCs with Aβ oligomers also result in β-catenin phosphorylation and reduced neurogenesis.

Further investigation in this area is necessary to fully understand the role of GPCs in neurogenesis under normal and pathological conditions, in particular, whether increasing levels of neurogenesis in AD might help to reduce the progression of the disease.

References:
1. He, P, Shen, Y. Interruption of b-catenin signaling reduces neurogenesis in Alzheimer´s disease. J. Neurosci. 29, 6545-57 (2009). Abstract

2. De Ferrari, G.V., Inestrosa, N.C. Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev 33, 1-12 (2000). Abstract

3. Inestrosa, N.C., Toledo, E.M. The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease. Mol Neurodegener 3, 9 (2008). Abstract

4. Lie, D.C. et al. Wnt signalling regulates adult hippocampal neurogenesis. Nature 437, 1370-5 (2005). Abstract

View all comments by Nibaldo Inestrosa

This paper by He and Shen is of great interest for several reasons. The first is that the authors address the link between neurogenesis and Alzheimer disease (AD) by studying the cell fate of neural progenitors isolated from AD autopsy specimens. The second is that this study, unlike many others, is not focused on a specialized “neurogenic niche” of the adult brain but rather the cerebral cortex. This brings me to a third reason: the attention to the role of Wnt/β-catenin signaling in the fate specification of cortical multipotent progenitor cells. Wnt/β-catenin signaling is known to promote cell fate specification in the developing cortex (1), and it is also known to be impaired in AD (2,3).

He and Shen report that glial precursor cells (GPCs) isolated from AD cortices exhibit reduced differentiation toward neurons compared with GPCs from healthy controls. This phenotype is causally related to an increased GSK-3β activity with ensuing phosphorylation of β-catenin (i.e., β-catenin degradation). It is very nice that the authors demonstrate that in GPCs...  Read more

This paper by He and Shen is of great interest for several reasons. The first is that the authors address the link between neurogenesis and Alzheimer disease (AD) by studying the cell fate of neural progenitors isolated from AD autopsy specimens. The second is that this study, unlike many others, is not focused on a specialized “neurogenic niche” of the adult brain but rather the cerebral cortex. This brings me to a third reason: the attention to the role of Wnt/β-catenin signaling in the fate specification of cortical multipotent progenitor cells. Wnt/β-catenin signaling is known to promote cell fate specification in the developing cortex (1), and it is also known to be impaired in AD (2,3).

He and Shen report that glial precursor cells (GPCs) isolated from AD cortices exhibit reduced differentiation toward neurons compared with GPCs from healthy controls. This phenotype is causally related to an increased GSK-3β activity with ensuing phosphorylation of β-catenin (i.e., β-catenin degradation). It is very nice that the authors demonstrate that in GPCs from APP23 transgenic mice, which recapitulate the AD neurogenetic deficit, knockdown of GSK-3β leads to the rescue of β-catenin levels and increases the expression of the proneuronal gene Ngn2.

Finally, the authors demonstrate that treating GPCs from healthy controls with synthetic β amyloid (Aβ) results in the apoptotic death of precursor cells belonging to the neuronal lineage. This is consistent with some previous studies (4,5), but (apparently) in contrast with other work (including my own) showing that Aβ might influence the fate of progenitor cells, driving their differentiation towards a neuronal lineage (6,7). I suggest that particular culture conditions might commit precursor cells to a specific phenotype prior to Aβ exposure, thus precluding the differentiating effect of the peptide. In addition, the degree of differentiation of precursor cells is likely to depend on the type of culture (e.g., plating versus floating, presence or absence of mitogens in the medium), which may produce “late neuronal precursors” that are sensitive to Aβ toxicity. Hence, Aβ might suppress a pro-survival pathway (i.e., Wnt/β-catenin signaling) in newborn neurons as it does in mature neurons (4,5), rather than impede neuronal differentiation.

I believe that further work is required to assess whether factors other than Aβ are responsible for suppressing neuronal differentiation in GPCs from AD. Nevertheless, it is quite clear that drugs able to rescue β-catenin signaling might help to sustain the neuronal progeny originating from GPCs.

References:
1. 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

2. De Ferrari, G.V., Inestrosa, N.C. Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev 2000; 33: 1-12. Abstract

3. 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

4. Haughey NJ, Liu D, Nath A, Borchard AC, Mattson MP. Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease. Neuromolecular Med. 2002;1(2):125-35. Abstract

5. Verret L, Jankowsky JL, Xu GM, Borchelt DR, Rampon C. Alzheimer's-type amyloidosis in transgenic mice impairs survival of newborn neurons derived from adult hippocampal neurogenesis. J Neurosci. 2007 Jun 20;27(25):6771-80. Abstract

6. López-Toledano MA, Shelanski ML. Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci. 2004 Jun 9;24(23):5439-44. Abstract

7. Calafiore M, Battaglia G, Zappalà A, Trovato-Salinaro E, Caraci F, Caruso M, Vancheri C, Sortino MA, Nicoletti F, Copani A. Progenitor cells from the adult mouse brain acquire a neuronal phenotype in response to beta-amyloid. Neurobiol Aging. 2006 Apr;27(4):606-13. Abstract

View all comments by Agata Copani

Editor's note: This comment contains a diagram which is also linked below in the text.

Alzheimer disease is principally characterized by a gradual and hierarchical decline in cognition, an impairment that correlates with accumulation of amyloid plaques and neurodegeneration in regions of the brain involved in higher cognitive function, such as the frontal cortex. The hippocampus represents a structure where neuroplasticity is maintained throughout life and is believed to be impaired in AD. This plasticity plays an important role in memory and response to injury. Despite extensive investigation, a mechanistic understanding of AD pathogenesis on hippocampal plasticity remains unclear. Unknown is whether hippocampal impairment is driven by cell-autonomous or non-cell autonomous mechanisms (or both). A negative correlation has been established between plaque formation and/or microglia-mediated neuroinflammation and hippocampal neurogenesis. Additionally, we have previously demonstrated that...  Read more

Editor's note: This comment contains a diagram which is also linked below in the text.

Alzheimer disease is principally characterized by a gradual and hierarchical decline in cognition, an impairment that correlates with accumulation of amyloid plaques and neurodegeneration in regions of the brain involved in higher cognitive function, such as the frontal cortex. The hippocampus represents a structure where neuroplasticity is maintained throughout life and is believed to be impaired in AD. This plasticity plays an important role in memory and response to injury. Despite extensive investigation, a mechanistic understanding of AD pathogenesis on hippocampal plasticity remains unclear. Unknown is whether hippocampal impairment is driven by cell-autonomous or non-cell autonomous mechanisms (or both). A negative correlation has been established between plaque formation and/or microglia-mediated neuroinflammation and hippocampal neurogenesis. Additionally, we have previously demonstrated that introduction of an FAD-associated mutant PS1 (L286V) into PC-12 cells, affects the Wnt signaling cascade (Teo et al., 2005), and is sufficient to inhibit neurite outgrowth and thus neuronal maturation (Guo et al., 1997; Teo et al., 2005).

In this paper, He and Shen demonstrate that Wnt/β-catenin signaling is disrupted in both mouse and human glial progenitor cells (GPC), in an in vitro model of neuronal plasticity. They observed a decrease in neuronal differentiation of AD GPCs in vitro that could in part be explained by an increase in apoptosis, as neuronal cell death can be triggered by Aβ. Furthermore, the authors claim that this aberrant Wnt signaling is responsible for significantly decreased neuronal differentiation of AD GPCs compared with normal GPCs in culture. How well this or any other in vitro model system recapitulates neurogenesis in vivo is unclear. Despite demonstrating a decrease in the levels of “un-phosphorylated β-catenin,” which they associate with decreased Wnt signaling, He and Shen provide no direct evidence for a decrease in Wnt/β-catenin-driven transcription (Topflash reporter, gene expression changes, e.g., Axin2 decrease). On the contrary, in our earlier studies, the PS1 (L286V) mutation caused an increase in Wnt/β-catenin-driven transcription as judged by both Topflash assay and gene expression analysis. Of further interest is evidence that increased Wnt signaling may be more generally associated with aging (Liu et al., 2007; Brack et al., 2007).

Aberrant Wnt signaling has previously been speculated to play a role in AD neuronal degeneration. However, the complexity of the Wnt signaling pathway has complicated this analysis. The Wnt/β-catenin pathway is critical at various stages during neural development and has been shown to regulate both the maintenance of potency, as well as direct neural differentiation, of embryonic stem cells and neural stem cells. We have recently developed a model to explain these divergent responses to activation of Wnt/β-catenin signaling. The model posits that β-catenin/CBP-mediated transcription is critical for maintenance of potency, whereas a switch to β-catenin/p300-mediated transcription is the first critical step to commitment to a differentiative program with more limited potency (Teo et al., 2005; Miyabayshi et al., 2007; see diagram).

In summation, we would like to propose a model of AD that takes into account the various results published to date (see diagram). Wnt signaling is critical in both neuronal development and maintenance and plasticity of the adult brain. We believe that the proper regulation of maintenance and plasticity in the adult brain is governed by the equilibrium between Wnt/β-catenin/CBP and Wnt/β-catenin/p300 driven gene transcription. There are undoubtedly a number of mechanisms (PS1 mutations, APP mutations, increased Aβ deposition, etc.) that can disrupt this equilibrium, thereby leading to decreased maintenance and plasticity and increased neuronal cell death, tipping the balance toward an enhanced rate of cognitive decline. Therapeutic strategies that restore the balance required for normal maintenance and plasticity may be very useful to treat AD and quite possibly the cognitive decline associated with aging.

References:
Guo Q, Sopher BL, Furukawa K, Pham DG, Robinson N, Martin GM, Mattson MP. Alzheimer's presenilin mutation sensitizes neural cells to apoptosis induced by trophic factor withdrawal and amyloid beta-peptide: involvement of calcium and oxyradicals. J Neurosci. 1997 Jun 1;17(11):4212-22. Abstract

Liu H, Fergusson MM, Castilho RM, Liu J, Cao L, Chen J, Malide D, Rovira II, Schimel D, Kuo CJ, Gutkind JS, Hwang PM, Finkel T. Augmented Wnt signaling in a mammalian model of accelerated aging. Science. 2007 Aug 10;317(5839):803-6. Abstract

Brack AS, Conboy MJ, Roy S, Lee M, Kuo CJ, Keller C, Rando TA. Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007 Aug 10;317(5839):807-10. Abstract

Miyabayashi T, Teo JL, Yamamoto M, McMillan M, Nguyen C, Kahn M. Wnt/beta-catenin/CBP signaling maintains long-term murine embryonic stem cell pluripotency. Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5668-73. Abstract

Teo JL, Ma H, Nguyen C, Lam C, Kahn M. Specific inhibition of CBP/beta-catenin interaction rescues defects in neuronal differentiation caused by a presenilin-1 mutation. Proc Natl Acad Sci U S A. 2005 Aug 23;102(34):12171-6. Abstract

View all comments by Michael Kahn
View all comments by Agnes Lukaszewicz

A Mediterranean diet is difficult to follow in the U.S.

View all comments by Bruce Miller