Notch Your Average Joe—Grounds for PS1 Neurogenesis Inhibition?

Notch, that pesky “other” γ-secretase substrate, mediates adult neurogenesis defects attributed to presenilin-1 (PS1) mutations, according to a study in this week’s Journal of Neuroscience. Sangram Sisodia and colleagues at the University of Chicago report that several PS1 mutants inhibit self-renewal and disturb differentiation of subventricular zone (SVZ) neural progenitor cells in the adult mouse brain. Furthermore, Notch signaling fizzles in mutant PS1-expressing SVZ progenitors, but restoring it through expression of constitutively active Notch rescued neurogenesis.

“It’s an excellent mechanistic analysis of the disruptions in Notch signaling caused by FAD-linked PS1 mutations,” said Roberta Brinton of the University of Southern California, Los Angeles, who studies neurogenesis in AD but was not involved with the study. “The fact that this is seen in the SVZ neurons clearly will have an impact on regenerative capability within zones of the brain that are being regenerated by the SV neurons, like the olfactory system, or the cerebral cortex in the event of injury.” Sisodia was less certain that the finding will have any bearing on our understanding of AD pathology.

PS1, the major gene responsible for early onset familial AD, is essential for mouse embryonic neural development (Shen et al., 1997; Handler et al., 2000; Kim and Shen, 2008; and ARF related news story) and helps regulate neuronal differentiation during adult neurogenesis (Hitoshi et al., 2002). Studies in various strains of AD transgenic mice have shown that FAD-linked PS1 mutations impair adult neurogenesis in the hippocampus (Wen et al., 2004 and ARF related news story; Wang et al., 2004; Chevallier et al., 2005). More recent analyses suggest that in some PS1-based AD models, neurogenesis declines before the mice develop obvious pathology (Demars et al., 2010).

Much of the work on PS1’s effects on adult neurogenesis has been done in mouse hippocampus—including research by Sisodia’s lab showing that mice with FAD-linked PS1 mutations have a blunted response to environmental enrichment, which typically ramps up production of new neurons (Choi et al., 2008 and ARF related news story).

In the present report, Sisodia and colleagues chose to analyze PS1’s effects on neurogenesis in the brain’s other major regeneration site, the subventricular zone. First author Karthikeyan Veeraraghavalu and colleagues transduced SVZ-derived neural progenitor cultures with lentiviruses carrying green fluorescent protein (GFP) and either human wild-type PS1 or FAD-linked PS1 mutant transgenes. Of the four PS1 transgenes tested, the ΔE9 and C410Y mutants most strongly inhibited progenitor self-renewal capacity, which was measured by counting progeny neurospheres that lit up green after lentiviral transduction. Using antibodies to mark the various cell types (e.g., MAP2 and βIII-tubulin for neuronal cells, GFAP for astrocytes), the researchers determined that the PS1 mutants prematurely drove differentiation toward a neuronal lineage.

The researchers confirmed these observations in vivo. Bromodeoxyuridine labeling studies showed that PS1ΔE9 transgenic mice have fewer SVZ progenitors than do wild-type PS1 littermates, and cultured SVZ progenitors from the PS1ΔE9 mice differentiated more quickly toward the neuronal lineage.

The findings reveal a key difference between how PS1 impacts neurogenesis in the SVZ versus in the hippocampus, Sisodia said. In his lab’s previous study (Choi et al., 2008), hippocampal neural progenitors expressing FAD-linked PS1 mutants had normal proliferation and differentiation despite showing a weaker response to environmental enrichment. This suggested that PS1’s effects on hippocampal neurogenesis are mediated by something non-cell-intrinsic—as it turned out, nearby microglia. In contrast, the present study suggests that PS1 stymies SVZ neurogenesis in a cell-intrinsic manner.

Signaling through Notch came to the fore as the likely cell-intrinsic mechanism, Sisodia said, given the critical role of this membrane protein in neuronal differentiation and as a major substrate of γ-secretase. Sure enough, his team found reduced transcription of genes in the Notch pathway, as well as diminished Notch-dependent reporter activity, in SVZ-derived neural progenitors from PS1ΔE9 mice, compared to wild-type PS1 progenitors.

To nail the role of Notch signaling in PS1’s influence on neurogenesis, the researchers once again used the lentivirus approach, this time shuttling a truncated, constitutively active Notch into the PS1ΔE9-expressing SVZ progenitors. This restored proliferation and differentiation in the progenitors back to wild-type form.

All told, the data suggest that “mutant presenilin-1 affects proliferation of SVZ progenitors through a mechanism that involves Notch signaling or lack thereof,” Sisodia told ARF.

Brinton praised the thoroughness of the new work. “I don't think you could have asked for a better experimental design and execution here,” she said. Though predominantly a basic science study, the research could have clinical relevance if, for instance, restoring the brain’s regenerative capacity can prevent or slow AD. That possibility appeared promising in her recent study of young 3xTg triple-transgenic mice, an AD model that has mutated PS1 (as well as pathogenic forms of tau and amyloid precursor protein). Brinton and colleagues found that allopregnanolone, a neurosteroid, relieved defects in neurogenesis and cognition if given to the mice before they develop AD-like pathology (Wang et al., 2010). “Identifying the specific points at which Notch is functioning in the regenerative process allows you to potentially target that point in the process, and not global Notch,” Brinton said.—Esther Landhuis

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References

News Citations

  1. Does APP Signaling, Even Diabetes, Depress Neurogenesis?
  2. Familial Alzheimer's Presenilin Gene Perturbs Neurogenesis?
  3. San Diego: Microglia Enter Enrichment Stage, Human Brain Imaging of Neurogenesis

Paper Citations

  1. Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997 May 16;89(4):629-39. PubMed.
  2. Handler M, Yang X, Shen J. Presenilin-1 regulates neuronal differentiation during neurogenesis. Development. 2000 Jun;127(12):2593-606. PubMed.
  3. Kim WY, Shen J. Presenilins are required for maintenance of neural stem cells in the developing brain. Mol Neurodegener. 2008;3:2. PubMed.
  4. Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev. 2002 Apr 1;16(7):846-58. PubMed.
  5. Wen PH, Hof PR, Chen X, Gluck K, Austin G, Younkin SG, Younkin LH, DeGasperi R, Gama Sosa MA, Robakis NK, Haroutunian V, Elder GA. 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.
  6. Wang R, Dineley KT, Sweatt JD, Zheng H. Presenilin 1 familial Alzheimer's disease mutation leads to defective associative learning and impaired adult neurogenesis. Neuroscience. 2004;126(2):305-12. PubMed.
  7. Chevallier NL, Soriano S, Kang DE, Masliah E, Hu G, Koo EH. Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation. Am J Pathol. 2005 Jul;167(1):151-9. PubMed.
  8. Demars M, Hu YS, Gadadhar A, Lazarov O. Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice. J Neurosci Res. 2010 Aug 1;88(10):2103-17. PubMed.
  9. Choi SH, Veeraraghavalu K, Lazarov O, Marler S, Ransohoff RM, Ramirez JM, Sisodia SS. Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron. 2008 Aug 28;59(4):568-80. PubMed.
  10. Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ, Thompson RF, Brinton RD. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6498-503. Epub 2010 Mar 15 PubMed.

Other Citations

  1. 3xTg triple-transgenic mice

Further Reading

Papers

  1. Handler M, Yang X, Shen J. Presenilin-1 regulates neuronal differentiation during neurogenesis. Development. 2000 Jun;127(12):2593-606. PubMed.
  2. Kim WY, Shen J. Presenilins are required for maintenance of neural stem cells in the developing brain. Mol Neurodegener. 2008;3:2. PubMed.
  3. Hitoshi S, Alexson T, Tropepe V, Donoviel D, Elia AJ, Nye JS, Conlon RA, Mak TW, Bernstein A, van der Kooy D. Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells. Genes Dev. 2002 Apr 1;16(7):846-58. PubMed.
  4. Wang JM, Singh C, Liu L, Irwin RW, Chen S, Chung EJ, Thompson RF, Brinton RD. Allopregnanolone reverses neurogenic and cognitive deficits in mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6498-503. Epub 2010 Mar 15 PubMed.
  5. Demars M, Hu YS, Gadadhar A, Lazarov O. Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice. J Neurosci Res. 2010 Aug 1;88(10):2103-17. PubMed.
  6. Choi SH, Veeraraghavalu K, Lazarov O, Marler S, Ransohoff RM, Ramirez JM, Sisodia SS. Non-cell-autonomous effects of presenilin 1 variants on enrichment-mediated hippocampal progenitor cell proliferation and differentiation. Neuron. 2008 Aug 28;59(4):568-80. PubMed.
  7. Wen PH, Hof PR, Chen X, Gluck K, Austin G, Younkin SG, Younkin LH, DeGasperi R, Gama Sosa MA, Robakis NK, Haroutunian V, Elder GA. 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.
  8. Chevallier NL, Soriano S, Kang DE, Masliah E, Hu G, Koo EH. Perturbed neurogenesis in the adult hippocampus associated with presenilin-1 A246E mutation. Am J Pathol. 2005 Jul;167(1):151-9. PubMed.

Primary Papers

  1. Veeraraghavalu K, Choi SH, Zhang X, Sisodia SS. Presenilin 1 mutants impair the self-renewal and differentiation of adult murine subventricular zone-neuronal progenitors via cell-autonomous mechanisms involving notch signaling. J Neurosci. 2010 May 19;30(20):6903-15. PubMed.

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