Mutations in presenilin could contribute to the memory loss of Alzheimer's disease by perturbing hippocampal neurogenesis, according to a study published in the August issue of Experimental Neurology. The researchers report that a familial AD-causing PS1 mutation can reduce the survival of nascent neurons in the hippocampus of transgenic mice.

In an earlier study, authors Gregory Elder, Paul Wen, and their colleagues at Mt. Sinai School of Medicine in New York City had found evidence to support a role for PS1 in hippocampal neurogenesis (Wen et al., 2002). They noted that a human wild-type PS1, but not an FAD-causing one, significantly boosted neurogenesis in the mouse hippocampus.

In the current study, first author Wen and colleagues found a result that was at once different and similar—the presence of a human wild-type transgene this time produced no change in neurogenesis relative to controls, while the same FAD-causing PS1 transgene (P117L) now produced a significant drop in new neurons in the hippocampus.

The authors have no immediate explanation for the discrepancies in their two experiments, noting only differences in the ages of the mice examined (three months versus two months in the earlier experiments) and the laboratory where the work was done. "However, what is clear is that in four separate experiments involving two independent lines for each transgene, the fractional survival of BrdU-labeled cells in FAD mutant animals was always decreased and that FAD mutant animals were always at a deficit of new neuron production compared to either PS1 wild-type transgenic or nontransgenic controls," the authors write.

The researchers do not believe that the reduced neurogenesis was a function of reduced progenitor proliferation or altered cell cycles, since there was no apparent difference in the numbers of labeled cells between groups in animals sacrificed at the end of the BrdU-labeling period. The reduction in new neurons in FAD-transgenic animals sacrificed some four weeks later suggests instead that the negative effect of the PS1 mutation is on the survival of the new cells, argue the authors.

Interestingly, the authors did not initially set out in this experiment to confirm—or complicate—their previous findings. Instead, they had hypothesized that by raising the mice in enriched environments, which are known to increase hippocampal neurogenesis, they might tease out effects of the mutation. In fact, they found no evidence for such an effect.

Entering the realm of speculation, how might a PS1 mutation affect survival? Mutant PS1 in the progenitor cells and/or their offspring in the human hippocampus would have the opportunity to disrupt neurogenesis. But in these experiments, the transgene was targeted to the mouse nervous system using a neuron-specific enolase transgene, meaning that the human PS1 genes, be they wild-type or FAD, were not expressed in the progenitor cells. And yet, the authors saw an effect of the FAD PS1 mutant gene, suggesting that it had to exert its effect from other cells.

The authors note that their FAD-transgenic mice produced higher amounts of Aβ42, but not Aβ40, than did control animals or wild-type transgenics. But the authors also suggest that nearby cells such as the adult granule cells could mediate reduced survival of neural precursors via PS1's interaction with proteins such as β-catenin and E-cadherin, and/or via PS1's role in γ-secretase cleavage of Notch.—Hakon Heimer

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  1. It has been assumed by many in the Alzheimer's disease (AD) field that presenilin-1 (PS1) FAD mutations represent a gain-of-function, in which altered processing of Abeta caused by the FAD mutants leads to neurodegeneration. However, this paper and the recent Neuron paper from Jie Shen's laboratory present compelling evidence that PS1 FAD mutations are actually loss-of-function mutations. Shen and colleagues showed that conditional knockouts of PS1 in the forebrain lead to many AD-like symptoms, both anatomical and behavioral, that are also seen in FAD mutant transgenic mice. In the present paper, Elder and colleagues demonstrate that the survival of BrdU-labeled neuronal progenitor cells is impaired in adult mice transgenic for a PS1 FAD mutation. This phenotype is similar to that described for a forebrain-specific PS1 knockout mouse, again suggesting a loss of function. These papers indicate that knowledge of the normal function of the presenilins almost certainly will enhance our understanding of AD neurodegeneration, in which PS1 function goes awry.

    View all comments by Rachael Neve

References

Paper Citations

  1. . 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.

Further Reading

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Primary Papers

  1. . 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.