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.
PubMed.
López-Toledano and Shelanski report that aggregated Aβ1-42 enhances the production of new neurons, detected by BrdU labeling and βIII tubulin immunoreactivity, in hippocampal cultures in vitro. These results are at odds with some previous data (1-3), but consistent with the finding of increased neurogenesis in the brains of Alzheimer’s disease (AD) patients (4), and with the emerging principle that acute and chronic neurodegenerative disorders stimulate neurogenesis in the adult brain, possibly as an adaptive response to injury (5). How injury translates into neurogenesis and whether neurogenesis in this setting yields functional neurons that can assume the functions of cells that die are major unanswered questions.
With respect to the mechanism that couples injury to neurogenesis, neurogenesis can occur at a distance from the site of pathology, and unilateral lesions can trigger neurogenesis bilaterally, providing at least tentative evidence for a humoral mediator. Several candidate mediators, including growth factors, hormones and neurotransmitters, are known to be capable of stimulating neurogenesis. However, it is intriguing to consider a possibility raised by this paper, namely, that specific disease products are involved. This might be one way to explain certain disease-specific features of injury-induced neurogenesis, such as where it occurs (subventricular zone, hippocampus or both) and, possibly, how newborn neurons are directed to different brain areas and induced to assume different phenotypic identities.
Regarding function, a recent paper from the laboratory of Dr. Jialing Liu at the University of California, San Francisco, (6) showed that cranial irradiation, which reduced the number of new neurons in the granule cell layer of the dentate gyrus by about 80 percent, also impaired behavioral recovery from global cerebral ischemia in gerbils, suggesting that inhibiting neurogenesis eliminated a recovery-promoting effect of cells normally produced in this setting. It will be important to conduct similar studies in mouse models of AD.
References:
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.
PubMed.
Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP.
Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease.
J Neurochem. 2002 Dec;83(6):1509-24.
PubMed.
Wen PH, Shao X, Shao Z, Hof PR, Wisniewski T, Kelley K, Friedrich VL, Ho L, Pasinetti GM, Shioi J, Robakis NK, Elder GA.
Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice.
Neurobiol Dis. 2002 Jun;10(1):8-19.
PubMed.
Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA.
Increased hippocampal neurogenesis in Alzheimer's disease.
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7.
PubMed.
Parent JM.
Injury-induced neurogenesis in the adult mammalian brain.
Neuroscientist. 2003 Aug;9(4):261-72.
PubMed.
Raber J, Fan Y, Matsumori Y, Liu Z, Weinstein PR, Fike JR, Liu J.
Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits.
Ann Neurol. 2004 Mar;55(3):381-9.
PubMed.
Because the production of new neurons from stem cells occurs in the adult brain and may decline during normal aging (1), and in light of emerging evidence that neurogenesis may play an important role in learning and memory (2), it is important to understand if and how neurogenesis is altered in AD. The generally accepted method for quantifying neurogenesis involves administration of bromo-deoxyuridine (BrdU) to animals or cultured cells to label newly generated cells; this is followed by immunostaining using antibodies against cell type-specific proteins to establish the phenotype of the cells that were produced from the stem cells. This method has not yet been applied to human AD and control subjects and so it is unclear whether there is an abnormality in neurogenesis in AD. In initial experiments designed to provide insight into how the pathogenic processes that occur in AD might influence neurogenesis, we found that Aβ 1-42 impairs neurogenesis in cultured human cortical neurospheres (3). Moreover, neurogenesis in the hippocampus of APP-mutant mice was significantly reduced in association with Aβ deposition. Additional findings suggested that Aβ impairs neurogenesis by inducing oxidative stress and disrupting cellular calcium homeostasis in the neural progenitor cells and newly-generated neurons (3), a mechanism similar to that by which Aβ may impair synaptic function and induce neuronal degeneration (4).
Based upon our findings and additional information, we propose that Aβ may adversely affect neurogenesis, and we suggest a possible role for such an abnormality in the cognitive dysfunction in AD. The possibility that neurogenesis is impaired in AD is consistent with epidemiological studies in humans and experiments in rodents that reveal associations between risk factors for AD and neurogenesis. In particular, three factors that may protect against AD (cognitive stimulation, exercise, dietary restriction) (5) have been shown to increase hippocampal neurogenesis in adult rodents (6, 7, 8). Moreover, adverse effects of Aβ oligomers on stem cells would be consistent with their adverse effects on synaptic plasticity and their cytotoxic actions on many different types of mitotic cells and postmitotic neurons.
In this paper, Lopez-Toledano and Shelanski found that Aβ 1-42 increases the number of β III tubulin-immunoreactive cells in dissociated cell cultures established from the striatum and hippocampus of embryonic rats and early postnatal mice, respectively. The authors conclude that Aβ 1-42 can enhance neurogenesis. Because our evidence suggests that Aβ 1-42 impairs neurogenesis in human cell cultures and in adult APP mutant mice, whereas Lopez-Toledano and Shelanski's findings suggest a stimulatory effect of Aβ 1-42, it becomes important to understand the reasons for the seemingly different results and their implications for AD. There were many differences in the culture systems employed, and also differences in the methods used to quantify neurogenesis, that could account for the results. Differences between the two culture systems include:
cell type: rodent striatal and hippocampal cells in Shelanski studies, human cortical cells in our studies;
dissociated cell cultures in their studies, neurosphere cultures in our studies;
different culture media and growth substrates;
aggregation state of Aβ (although generally similar methods were used to prepare the Aβ 1-42, there is considerable batch-to-batch variability in peptide aggregation kinetics).
We and others have found that dissociating neurospheres into a single-cell suspension prior to attachment to a substrate dramatically reduces the percentage of neurons that differentiate from progenitors, and that cell-cell contact and factors released from glia affect the process of neurogenesis. The cellular milieu in neurospheres may therefore be more reflective of the niche in which neural stem cells reside in vivo.
We evaluated neurogenesis using conventional BrdU-labeling methods, whereas Lopez-Toledano et al. counted β III tubulin-immunoreactive cells without establishing that they had arisen from progenitors during the time of cell culture. The results of the only experiment in which these authors did label cells with BrdU suggested a trend towards decreased neurogenesis in cells exposed to Ab 1-42 (Figure 2C in Lopez-Toledano et al.). Nevertheless, the overall increase in cells with a neuronal phenotype in cultures exposed to Aβ 1-42 is of considerable interest. One possible explanation for these results, given the well-established cytotoxic effects of Aβ, it that the Aβ 1-42 induced stress in the neural progenitor cells which, in turn, stimulated neurogenesis. The latter possibility is consistent with considerable evidence that various types of damage or stress to the brain can stimulate neurogenesis, possibly as a compensatory response designed to replace damaged neurons (9).
Of course much further work will be required to determine if, and to what extent, alterations in neurogenesis play a role in the pathogenesis of AD. Alas, dissecting the effects of Aβ from the effects produced by oxidative stress, inflammation, and other neuropathological contributors to the AD process in humans is a daunting task. However, a better understanding of how neurogenesis is altered in AD, and elucidation of the underlying cellular and molecular mechanisms, may lead to novel strategies for preventing and treating AD.
References:
Kuhn HG, Dickinson-Anson H, Gage FH.
Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation.
J Neurosci. 1996 Mar 15;16(6):2027-33.
PubMed.
Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E.
Neurogenesis in the adult is involved in the formation of trace memories.
Nature. 2001 Mar 15;410(6826):372-6.
PubMed.
Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP.
Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease.
J Neurochem. 2002 Dec;83(6):1509-24.
PubMed.
Mattson MP.
Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives.
Physiol Rev. 1997 Oct;77(4):1081-132.
PubMed.
Mayeux R.
Epidemiology of neurodegeneration.
Annu Rev Neurosci. 2003;26:81-104.
PubMed.
Kempermann G, Kuhn HG, Gage FH.
More hippocampal neurons in adult mice living in an enriched environment.
Nature. 1997 Apr 3;386(6624):493-5.
PubMed.
van Praag H, Kempermann G, Gage FH.
Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus.
Nat Neurosci. 1999 Mar;2(3):266-70.
PubMed.
Lee J, Duan W, Mattson MP.
Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice.
J Neurochem. 2002 Sep;82(6):1367-75.
PubMed.
Kokaia Z, Lindvall O.
Neurogenesis after ischaemic brain insults.
Curr Opin Neurobiol. 2003 Feb;13(1):127-32.
PubMed.
While Aβ toxicity has received much research focus, its physiological function was overlooked in the past. We have reported that neural stem cells (NSC) transplanted into amyloid precursor protein (APP)-transgenic mouse brain preferentially differentiated into astrocytes, and that over-expression or treatment with secreted APP induce glial differentiation of NSCs in vitro.
In the current study the authors found a neurogenic effect of Aβ on NSCs. Although some confusion may exist in the experiments, this study would mark a turning point in Aβ toxicity studies. In the first series of experiments, NSCs were treated only 24h with Aβ at different post-plating time points and the neurogenic stimulation of Aβ was found at 0 and 7 days post-plating. This experiment could be improved if the authors consider that the commitment of differentiation may occur in the first stage of differentiation, and spontaneous differentiation may takes more than 24 hours.
The author showed that the total number of the cell did not change (Fig 1C), the percentage of BrdU-positive cells did not change (Fig 2B) and the percentage of neuron increased by Aβ treatment. However, the percentage of neuron against BrdU-positive cell did not change by Aβ treatment. This result may be confusing. If the total number of cells and the percentage of BrdU-positive cell did not change, the number of BrdU should be the same between the control and Aβ treatment. Thus if the percentage of neurons is increased, the percentage of β -tubulin cell (neuron) against BrdU-positive cells should also be increased.
The authors also found that only the aggregated Aβ 1– 42 peptide had a neurogenic effect on the NSC progeny, and that only the oligomeric peptide (A o) and 1– 42 aggregated had a neurogenic effect when Aβ produced by the method of Dahlgren et al. (2002) was used. This result, neurogenic effect of Aeta 1– 42 aggregated peptide, may raise the question of why no neurogenesis is observed around the area of Aβ deposition in the Alzheimer’s brain. However, unfortunately the authors concluded that ‘the formation of new neurons is more likely to be induced by the “soluble” forms of Aβ than by the Aβ that has been organized into senile plaques.’
I would like to see a continuation of this line of studies, which may introduce a totally new concept, i.e., the dysfunction of NSC under Alzheimer’s disease pathology, to the field.
Neurogenesis in AD: Good, Bad or Ugly?
Propelled by the Democratic National Convention, stem cell research and its potential as a therapeutic for neurodegenerative diseases such as Alzheimer disease (AD) is back in the headlines. However, often lacking from such headlines is the innate capacity of “self” stem cells in the hippocampus to generate new neurons throughout our lifespan. This process, hippocampal neurogenesis, is rapidly gaining importance not only as a potential therapeutic avenue (i.e., replacement of damaged neurons) but also as a potential pathogenic mechanism (i.e., inability to generate new neurons) for disease. López-Toledano and Shelanski (2004) present exciting data demonstrating that aggregated Aβ1-42 leads to increases in new neuron production in hippocampal cultures in vitro. While these findings contrast those found by other groups (Haughey et al., 2002a,b), they are in accord with a recent report demonstrating increased neurogenesis in patients with AD (Jin et al., 2004). This apparent contradiction in results brings to light the very unclear the role of neurogenesis in AD. On the one hand, conditions that improve cognitive output and increase neurogenesis such as the presence of estrogen (Tanapat et al., 1999), enriched environment (Kempermann et al., 1998a,b) and exercise (van Praag et al., 1999) are associated with a decreased incidence of AD, and conditions that lead to declines in behavioral output and neurogenesis like depression (Malberg et al., 2000), stress (Gould and Tanapat, 1999), cholinergic dysfunction (Cooper-Kuhn et al., 2004) and aging (Kuhn et al., 1996; Kemperman et al., 1998a) are associated with increases in incidence of AD. However, on the other hand, brain injury, which is associated with increased incidence of AD, leads to increased hippocampal neurogenesis and caloric restriction (Lee et al., 2000), which increases neurogenesis, and is thought to be beneficial to normal subjects and protecting from many risk factors associated with AD (i.e., oxidative stress, inflammation, etc.), is detrimental or even lethal to the APP transgenic (Mattson, 2000). To complicate things further a recent study demonstrates that aged animals with higher levels of new cells in the hippocampus show lower cognitive performance than those animals with fewer cells (Bizon et al., 2004). Therefore, while the field seems to use increases or decreases in neurogenesis to fit the “so-called” detrimental role of Aβ in AD (if neurogenesis is increased it is associated with repair and if is decreased it is associated with declining cognition) based on the research in the field of hippocampal neurogenesis, the jury is still out on what the exact function of neurogenesis is and whether increases or decreases in neurogenesis would dictate benefit or detriment in AD.
References:
Bizon JL, Lee HJ, Gallagher M.
Neurogenesis in a rat model of age-related cognitive decline.
Aging Cell. 2004 Aug;3(4):227-34.
PubMed.
Cooper-Kuhn CM, Winkler J, Kuhn HG.
Decreased neurogenesis after cholinergic forebrain lesion in the adult rat.
J Neurosci Res. 2004 Jul 15;77(2):155-65.
PubMed.
Gould E, Tanapat P.
Stress and hippocampal neurogenesis.
Biol Psychiatry. 1999 Dec 1;46(11):1472-9.
PubMed.
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.
PubMed.
Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP.
Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease.
J Neurochem. 2002 Dec;83(6):1509-24.
PubMed.
Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA.
Increased hippocampal neurogenesis in Alzheimer's disease.
Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7.
PubMed.
Kempermann G, Brandon EP, Gage FH.
Environmental stimulation of 129/SvJ mice causes increased cell proliferation and neurogenesis in the adult dentate gyrus.
Curr Biol. 1998 Jul 30-Aug 13;8(16):939-42.
PubMed.
Kempermann G, Kuhn HG, Gage FH.
Experience-induced neurogenesis in the senescent dentate gyrus.
J Neurosci. 1998 May 1;18(9):3206-12.
PubMed.
Lee J, Duan W, Long JM, Ingram DK, Mattson MP.
Dietary restriction increases the number of newly generated neural cells, and induces BDNF expression, in the dentate gyrus of rats.
J Mol Neurosci. 2000 Oct;15(2):99-108.
PubMed.
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.
PubMed.
Malberg JE, Eisch AJ, Nestler EJ, Duman RS.
Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus.
J Neurosci. 2000 Dec 15;20(24):9104-10.
PubMed.
Mattson MP.
Neuroprotective signaling and the aging brain: take away my food and let me run.
Brain Res. 2000 Dec 15;886(1-2):47-53.
PubMed.
Tanapat P, Hastings NB, Reeves AJ, Gould E.
Estrogen stimulates a transient increase in the number of new neurons in the dentate gyrus of the adult female rat.
J Neurosci. 1999 Jul 15;19(14):5792-801.
PubMed.
van Praag H, Christie BR, Sejnowski TJ, Gage FH.
Running enhances neurogenesis, learning, and long-term potentiation in mice.
Proc Natl Acad Sci U S A. 1999 Nov 9;96(23):13427-31.
PubMed.
Comments
López-Toledano and Shelanski report that aggregated Aβ1-42 enhances the production of new neurons, detected by BrdU labeling and βIII tubulin immunoreactivity, in hippocampal cultures in vitro. These results are at odds with some previous data (1-3), but consistent with the finding of increased neurogenesis in the brains of Alzheimer’s disease (AD) patients (4), and with the emerging principle that acute and chronic neurodegenerative disorders stimulate neurogenesis in the adult brain, possibly as an adaptive response to injury (5). How injury translates into neurogenesis and whether neurogenesis in this setting yields functional neurons that can assume the functions of cells that die are major unanswered questions.
With respect to the mechanism that couples injury to neurogenesis, neurogenesis can occur at a distance from the site of pathology, and unilateral lesions can trigger neurogenesis bilaterally, providing at least tentative evidence for a humoral mediator. Several candidate mediators, including growth factors, hormones and neurotransmitters, are known to be capable of stimulating neurogenesis. However, it is intriguing to consider a possibility raised by this paper, namely, that specific disease products are involved. This might be one way to explain certain disease-specific features of injury-induced neurogenesis, such as where it occurs (subventricular zone, hippocampus or both) and, possibly, how newborn neurons are directed to different brain areas and induced to assume different phenotypic identities.
Regarding function, a recent paper from the laboratory of Dr. Jialing Liu at the University of California, San Francisco, (6) showed that cranial irradiation, which reduced the number of new neurons in the granule cell layer of the dentate gyrus by about 80 percent, also impaired behavioral recovery from global cerebral ischemia in gerbils, suggesting that inhibiting neurogenesis eliminated a recovery-promoting effect of cells normally produced in this setting. It will be important to conduct similar studies in mouse models of AD.
References:
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. PubMed.
Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem. 2002 Dec;83(6):1509-24. PubMed.
Wen PH, Shao X, Shao Z, Hof PR, Wisniewski T, Kelley K, Friedrich VL, Ho L, Pasinetti GM, Shioi J, Robakis NK, Elder GA. Overexpression of wild type but not an FAD mutant presenilin-1 promotes neurogenesis in the hippocampus of adult mice. Neurobiol Dis. 2002 Jun;10(1):8-19. PubMed.
Jin K, Peel AL, Mao XO, Xie L, Cottrell BA, Henshall DC, Greenberg DA. Increased hippocampal neurogenesis in Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Jan 6;101(1):343-7. PubMed.
Parent JM. Injury-induced neurogenesis in the adult mammalian brain. Neuroscientist. 2003 Aug;9(4):261-72. PubMed.
Raber J, Fan Y, Matsumori Y, Liu Z, Weinstein PR, Fike JR, Liu J. Irradiation attenuates neurogenesis and exacerbates ischemia-induced deficits. Ann Neurol. 2004 Mar;55(3):381-9. PubMed.
Johns Hopkins
Because the production of new neurons from stem cells occurs in the adult brain and may decline during normal aging (1), and in light of emerging evidence that neurogenesis may play an important role in learning and memory (2), it is important to understand if and how neurogenesis is altered in AD. The generally accepted method for quantifying neurogenesis involves administration of bromo-deoxyuridine (BrdU) to animals or cultured cells to label newly generated cells; this is followed by immunostaining using antibodies against cell type-specific proteins to establish the phenotype of the cells that were produced from the stem cells. This method has not yet been applied to human AD and control subjects and so it is unclear whether there is an abnormality in neurogenesis in AD. In initial experiments designed to provide insight into how the pathogenic processes that occur in AD might influence neurogenesis, we found that Aβ 1-42 impairs neurogenesis in cultured human cortical neurospheres (3). Moreover, neurogenesis in the hippocampus of APP-mutant mice was significantly reduced in association with Aβ deposition. Additional findings suggested that Aβ impairs neurogenesis by inducing oxidative stress and disrupting cellular calcium homeostasis in the neural progenitor cells and newly-generated neurons (3), a mechanism similar to that by which Aβ may impair synaptic function and induce neuronal degeneration (4).
Based upon our findings and additional information, we propose that Aβ may adversely affect neurogenesis, and we suggest a possible role for such an abnormality in the cognitive dysfunction in AD. The possibility that neurogenesis is impaired in AD is consistent with epidemiological studies in humans and experiments in rodents that reveal associations between risk factors for AD and neurogenesis. In particular, three factors that may protect against AD (cognitive stimulation, exercise, dietary restriction) (5) have been shown to increase hippocampal neurogenesis in adult rodents (6, 7, 8). Moreover, adverse effects of Aβ oligomers on stem cells would be consistent with their adverse effects on synaptic plasticity and their cytotoxic actions on many different types of mitotic cells and postmitotic neurons.
In this paper, Lopez-Toledano and Shelanski found that Aβ 1-42 increases the number of β III tubulin-immunoreactive cells in dissociated cell cultures established from the striatum and hippocampus of embryonic rats and early postnatal mice, respectively. The authors conclude that Aβ 1-42 can enhance neurogenesis. Because our evidence suggests that Aβ 1-42 impairs neurogenesis in human cell cultures and in adult APP mutant mice, whereas Lopez-Toledano and Shelanski's findings suggest a stimulatory effect of Aβ 1-42, it becomes important to understand the reasons for the seemingly different results and their implications for AD. There were many differences in the culture systems employed, and also differences in the methods used to quantify neurogenesis, that could account for the results. Differences between the two culture systems include:
We and others have found that dissociating neurospheres into a single-cell suspension prior to attachment to a substrate dramatically reduces the percentage of neurons that differentiate from progenitors, and that cell-cell contact and factors released from glia affect the process of neurogenesis. The cellular milieu in neurospheres may therefore be more reflective of the niche in which neural stem cells reside in vivo.
We evaluated neurogenesis using conventional BrdU-labeling methods, whereas Lopez-Toledano et al. counted β III tubulin-immunoreactive cells without establishing that they had arisen from progenitors during the time of cell culture. The results of the only experiment in which these authors did label cells with BrdU suggested a trend towards decreased neurogenesis in cells exposed to Ab 1-42 (Figure 2C in Lopez-Toledano et al.). Nevertheless, the overall increase in cells with a neuronal phenotype in cultures exposed to Aβ 1-42 is of considerable interest. One possible explanation for these results, given the well-established cytotoxic effects of Aβ, it that the Aβ 1-42 induced stress in the neural progenitor cells which, in turn, stimulated neurogenesis. The latter possibility is consistent with considerable evidence that various types of damage or stress to the brain can stimulate neurogenesis, possibly as a compensatory response designed to replace damaged neurons (9).
Of course much further work will be required to determine if, and to what extent, alterations in neurogenesis play a role in the pathogenesis of AD. Alas, dissecting the effects of Aβ from the effects produced by oxidative stress, inflammation, and other neuropathological contributors to the AD process in humans is a daunting task. However, a better understanding of how neurogenesis is altered in AD, and elucidation of the underlying cellular and molecular mechanisms, may lead to novel strategies for preventing and treating AD.
References:
Kuhn HG, Dickinson-Anson H, Gage FH. Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci. 1996 Mar 15;16(6):2027-33. PubMed.
Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E. Neurogenesis in the adult is involved in the formation of trace memories. Nature. 2001 Mar 15;410(6826):372-6. PubMed.
Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem. 2002 Dec;83(6):1509-24. PubMed.
Mattson MP. Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives. Physiol Rev. 1997 Oct;77(4):1081-132. PubMed.
Mayeux R. Epidemiology of neurodegeneration. Annu Rev Neurosci. 2003;26:81-104. PubMed.
Kempermann G, Kuhn HG, Gage FH. More hippocampal neurons in adult mice living in an enriched environment. Nature. 1997 Apr 3;386(6624):493-5. PubMed.
van Praag H, Kempermann G, Gage FH. Running increases cell proliferation and neurogenesis in the adult mouse dentate gyrus. Nat Neurosci. 1999 Mar;2(3):266-70. PubMed.
Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem. 2002 Sep;82(6):1367-75. PubMed.
Kokaia Z, Lindvall O. Neurogenesis after ischaemic brain insults. Curr Opin Neurobiol. 2003 Feb;13(1):127-32. PubMed.
It would be good to see the response(s) of the authors.
University of Central Florida
While Aβ toxicity has received much research focus, its physiological function was overlooked in the past. We have reported that neural stem cells (NSC) transplanted into amyloid precursor protein (APP)-transgenic mouse brain preferentially differentiated into astrocytes, and that over-expression or treatment with secreted APP induce glial differentiation of NSCs in vitro.
In the current study the authors found a neurogenic effect of Aβ on NSCs. Although some confusion may exist in the experiments, this study would mark a turning point in Aβ toxicity studies. In the first series of experiments, NSCs were treated only 24h with Aβ at different post-plating time points and the neurogenic stimulation of Aβ was found at 0 and 7 days post-plating. This experiment could be improved if the authors consider that the commitment of differentiation may occur in the first stage of differentiation, and spontaneous differentiation may takes more than 24 hours.
The author showed that the total number of the cell did not change (Fig 1C), the percentage of BrdU-positive cells did not change (Fig 2B) and the percentage of neuron increased by Aβ treatment. However, the percentage of neuron against BrdU-positive cell did not change by Aβ treatment. This result may be confusing. If the total number of cells and the percentage of BrdU-positive cell did not change, the number of BrdU should be the same between the control and Aβ treatment. Thus if the percentage of neurons is increased, the percentage of β -tubulin cell (neuron) against BrdU-positive cells should also be increased.
The authors also found that only the aggregated Aβ 1– 42 peptide had a neurogenic effect on the NSC progeny, and that only the oligomeric peptide (A o) and 1– 42 aggregated had a neurogenic effect when Aβ produced by the method of Dahlgren et al. (2002) was used. This result, neurogenic effect of Aeta 1– 42 aggregated peptide, may raise the question of why no neurogenesis is observed around the area of Aβ deposition in the Alzheimer’s brain. However, unfortunately the authors concluded that ‘the formation of new neurons is more likely to be induced by the “soluble” forms of Aβ than by the Aβ that has been organized into senile plaques.’
I would like to see a continuation of this line of studies, which may introduce a totally new concept, i.e., the dysfunction of NSC under Alzheimer’s disease pathology, to the field.
CWRU
Neurogenesis in AD: Good, Bad or Ugly?
Propelled by the Democratic National Convention, stem cell research and its potential as a therapeutic for neurodegenerative diseases such as Alzheimer disease (AD) is back in the headlines. However, often lacking from such headlines is the innate capacity of “self” stem cells in the hippocampus to generate new neurons throughout our lifespan. This process, hippocampal neurogenesis, is rapidly gaining importance not only as a potential therapeutic avenue (i.e., replacement of damaged neurons) but also as a potential pathogenic mechanism (i.e., inability to generate new neurons) for disease. López-Toledano and Shelanski (2004) present exciting data demonstrating that aggregated Aβ1-42 leads to increases in new neuron production in hippocampal cultures in vitro. While these findings contrast those found by other groups (Haughey et al., 2002a,b), they are in accord with a recent report demonstrating increased neurogenesis in patients with AD (Jin et al., 2004). This apparent contradiction in results brings to light the very unclear the role of neurogenesis in AD. On the one hand, conditions that improve cognitive output and increase neurogenesis such as the presence of estrogen (Tanapat et al., 1999), enriched environment (Kempermann et al., 1998a,b) and exercise (van Praag et al., 1999) are associated with a decreased incidence of AD, and conditions that lead to declines in behavioral output and neurogenesis like depression (Malberg et al., 2000), stress (Gould and Tanapat, 1999), cholinergic dysfunction (Cooper-Kuhn et al., 2004) and aging (Kuhn et al., 1996; Kemperman et al., 1998a) are associated with increases in incidence of AD. However, on the other hand, brain injury, which is associated with increased incidence of AD, leads to increased hippocampal neurogenesis and caloric restriction (Lee et al., 2000), which increases neurogenesis, and is thought to be beneficial to normal subjects and protecting from many risk factors associated with AD (i.e., oxidative stress, inflammation, etc.), is detrimental or even lethal to the APP transgenic (Mattson, 2000). To complicate things further a recent study demonstrates that aged animals with higher levels of new cells in the hippocampus show lower cognitive performance than those animals with fewer cells (Bizon et al., 2004). Therefore, while the field seems to use increases or decreases in neurogenesis to fit the “so-called” detrimental role of Aβ in AD (if neurogenesis is increased it is associated with repair and if is decreased it is associated with declining cognition) based on the research in the field of hippocampal neurogenesis, the jury is still out on what the exact function of neurogenesis is and whether increases or decreases in neurogenesis would dictate benefit or detriment in AD.
References:
Bizon JL, Lee HJ, Gallagher M. Neurogenesis in a rat model of age-related cognitive decline. Aging Cell. 2004 Aug;3(4):227-34. PubMed.
Cooper-Kuhn CM, Winkler J, Kuhn HG. Decreased neurogenesis after cholinergic forebrain lesion in the adult rat. J Neurosci Res. 2004 Jul 15;77(2):155-65. PubMed.
Gould E, Tanapat P. Stress and hippocampal neurogenesis. Biol Psychiatry. 1999 Dec 1;46(11):1472-9. PubMed.
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. PubMed.
Haughey NJ, Nath A, Chan SL, Borchard AC, Rao MS, Mattson MP. Disruption of neurogenesis by amyloid beta-peptide, and perturbed neural progenitor cell homeostasis, in models of Alzheimer's disease. J Neurochem. 2002 Dec;83(6):1509-24. PubMed.
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