The oldest and the youngest people are often the most vulnerable to disease. The same might be true for cells. Alzheimer disease (AD) primarily attacks those aged 65 and older, robbing them of their 65-year-old neurons—and their memories. But immature neurons might also be at risk in AD, according to a paper in this week’s Journal of Neuroscience. Ping He and senior author Yong Shen, both at Sun Health Research Institute, Sun City, Arizona, report that brain neuronal progenitors isolated from Alzheimer patients have trouble making new neurons. “We found that proliferation is fine but progenitor cells isolated from AD brain cannot differentiate into neurons,” Shen told ARF. The researchers traced the problem to amyloid-β (Aβ), which seems to block cellular signals that are essential for neurogenesis. “It is not only that neurons are degenerating in AD, but neural progenitors are suffering too,” said Shen.

Neurogenesis in the adult human brain is extremely limited. Nonetheless, recent evidence suggests that adult-born neurons can significantly contribute to function, playing roles in memory formation (see ARF related news story on Trouche et al., 2009) and even in the action of some anti-depressants (see ARF related news story). Some researchers hope that neurogenesis, either natural or from transplanted stem cells, might one day offer a way to treat neurodegenerative diseases such as AD and Parkinson’s. But Shen’s work suggests that might not be so straightforward. “There may be a pathological environment in the Alzheimer’s brain that is not suitable for stem cells. What’s more, signal transduction pathways are interrupted, and that’s not good either,” he told ARF.

Shen and He identified the neurogenesis problem when studying precursor cells from AD and age-matched healthy control brains. From the cerebral cortex they isolated glial precursor cells (GPCs), which can give rise to the three major cell types of the brain—neurons, glia, and oligodendrocytes. The researchers found that when grown in culture, GPCs from AD autopsy tissue made significantly fewer neurons than the same cells isolated from healthy tissue. GPCs and their progeny also made more Aβ40/42 than control cells, suggesting that the peptide might somehow prevent progenitors from forming neurons. To test this idea, He incubated GPCs from healthy brain with aggregates of Aβ (the peptide was incubated overnight). The treatment induced apoptosis, or programmed cell death, in cells that began to express neuron or oligodendrocyte markers, suggesting that Aβ is toxic to these fledgling cell types. In contrast, the peptide seemed to have no effect on cells differentiating toward glia. “That may help explain why there is gliosis, or activated glial cells, in the AD brain,” said Shen.

The progeny of GPC cells isolated from AD brain also had reduced expression of proneuronal genes, such as neurogenin 2 (Ngn2) and neurogenic differentiation factor 1, suggesting that pro-neuronal signals are suppressed in those cells. Since Wnt/β-catenin signaling is a major driving force in adult neurogenesis (see ARF related news story on Lie et al., 2005), He looked to see if this pathway is perturbed in progenitors from AD brain. He found that levels of Wnt and its receptor Frizzled appeared normal, but that the dynamics of β-catenin, a major downstream transcription factor, were far from it. The level of active β-catenin was significantly lower in GPCs from AD brain (and their progeny) compared to cells from normal healthy brains. In contrast, levels of inactive phosphorylated β-catenin, and its kinase, GSK-3β, were much higher than in control cells. Transfecting AD GPCs with β-catenin restored proneuronal gene expression, while silencing β-catenin in normal healthy GPCs had the opposite effect, confirming the pivotal role played by this transcription factor. Furthermore, by treating GPCs from healthy controls with Aβ aggregates, He was able to evoke an AD GPC-type expression profile, with elevated GSK-3β and phosphorylation of β-catenin, again suggesting that the peptide is bad news for neuronal differentiation. The authors also found that neurogenesis from GPCs is perturbed in APP23 transgenic mice, which overexpress Aβ, and that β-catenin signaling is attenuated in mouse progenitors as in GPCs from human AD brain. All told, the results suggest that the Aβ in the AD brain may create a noxious environment for adult neurogenesis.

This is not the first time AD has been linked to neurogenesis. Notch signaling, which requires the same presenilin that processes Aβ precursor protein (APP), helps drive adult neurogenesis (see ARF related news story on Breunig et al., 2007). Presenilin mutations may suppress it (see ARF related news story on Wen et al., 2004) even when driven by environmental enrichment (see ARF related news story), a known promoter of neurogenesis in mammals. The results also tie in with previous findings showing that mutant forms of presenilin destabilize β-catenin (see ARF related news story) and that APP signaling can suppress neurogenesis (see ARF related news story on Ma et al., 2008) .

Whether any of these APP/PS effects are solely due to production of Aβ is unclear, said Shen. He plans to study signal transduction in neural progenitors to see how it relates to APP signaling and whether tweaking various signaling pathways might help improve adult neurogenesis. In this regard, some advances have been made with embryonic stem cells. Small molecules that activate GSK-3β have been shown to activate neurogenesis, for example (see ARF related news story), and in the May 17 Nature Neuroscience online, researchers led by Freda Miller at the Hospital for Sick Children, Toronto, Canada, report on two factors that regulate neurogenesis in mouse embryonic cortical precursors. First author Andree Gauthier-Fisher and colleagues found that knocking down Lfc, a guanine nucleotide exchange factor, blocks neurogenesis, while knocking down the Lfc negative regulator Tctex-1, on the contrary boosts neurogenesis. Unlike Aβ, which seems to act on the differentiation phase of neurogenesis, Lfc seems to work on the proliferative phase, helping to orient the mitotic spindles that are necessary for cell division.—Tom Fagan


  1. 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.


    . Interruption of beta-catenin signaling reduces neurogenesis in Alzheimer's disease. J Neurosci. 2009 May 20;29(20):6545-57. PubMed.

    . Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev. 2000 Aug;33(1):1-12. PubMed.

    . The role of Wnt signaling in neuronal dysfunction in Alzheimer's Disease. Mol Neurodegener. 2008;3:9. PubMed.

    . Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005 Oct 27;437(7063):1370-5. PubMed.

  2. 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.


    . The Wnt/beta-catenin pathway directs neuronal differentiation of cortical neural precursor cells. Development. 2004 Jun;131(12):2791-801. PubMed.

    . Wnt signaling function in Alzheimer's disease. Brain Res Brain Res Rev. 2000 Aug;33(1):1-12. PubMed.

    . Induction of Dickkopf-1, a negative modulator of the Wnt pathway, is associated with neuronal degeneration in Alzheimer's brain. J Neurosci. 2004 Jun 30;24(26):6021-7. PubMed.

    . 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. PubMed.

    . 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. PubMed.

    . Neurogenic effect of beta-amyloid peptide in the development of neural stem cells. J Neurosci. 2004 Jun 9;24(23):5439-44. PubMed.

    . Progenitor cells from the adult mouse brain acquire a neuronal phenotype in response to beta-amyloid. Neurobiol Aging. 2006 Apr;27(4):606-13. PubMed.

  3. 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.


    . 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. PubMed.

    . Augmented Wnt signaling in a mammalian model of accelerated aging. Science. 2007 Aug 10;317(5839):803-6. PubMed.

    . Increased Wnt signaling during aging alters muscle stem cell fate and increases fibrosis. Science. 2007 Aug 10;317(5839):807-10. PubMed.

    . 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. PubMed.

    . 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. PubMed.

Make a Comment

To make a comment you must login or register.


News Citations

  1. Circuit Menders? Neurogenesis, Stem Cells Show Potential
  2. New York: Catalyst Conference on Stem Cells, Cognitive Aging, and AD
  3. Adult Neurogenesis—A Win Wnt Situation?
  4. Postnatal Neurogenesis Tied in with Presenilins, Ephrin Signaling
  5. Familial Alzheimer's Presenilin Gene Perturbs Neurogenesis?
  6. San Diego: Microglia Enter Enrichment Stage, Human Brain Imaging of Neurogenesis
  7. Mutant PS1 Destabilizes β-Catenin
  8. Does APP Signaling, Even Diabetes, Depress Neurogenesis?
  9. Small Molecules Turn Stem Cells into Neurons, Targeting GSK3β

Paper Citations

  1. . Recruitment of adult-generated neurons into functional hippocampal networks contributes to updating and strengthening of spatial memory. Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5919-24. PubMed.
  2. . Wnt signalling regulates adult hippocampal neurogenesis. Nature. 2005 Oct 27;437(7063):1370-5. PubMed.
  3. . Notch regulates cell fate and dendrite morphology of newborn neurons in the postnatal dentate gyrus. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20558-63. PubMed.
  4. . The presenilin-1 familial Alzheimer disease mutant P117L impairs neurogenesis in the hippocampus of adult mice. Exp Neurol. 2004 Aug;188(2):224-37. PubMed.
  5. . A TAG1-APP signalling pathway through Fe65 negatively modulates neurogenesis. Nat Cell Biol. 2008 Mar;10(3):283-94. PubMed.

Further Reading

Primary Papers

  1. . Lfc and Tctex-1 regulate the genesis of neurons from cortical precursor cells. Nat Neurosci. 2009 Jun;12(6):735-44. PubMed.
  2. . Interruption of beta-catenin signaling reduces neurogenesis in Alzheimer's disease. J Neurosci. 2009 May 20;29(20):6545-57. PubMed.