Katsutoshi Furukawa and colleagues at the National Institute on Aging, Baltimore, report in the June 9 early online PNAS that Notch signaling is required for LTP in adult mice. This finding is relevant to AD researchers because inhibiting γ-secretase, the protein complex responsible for generating the Aβ peptide, could be an attractive therapeutic strategy for Alzheimer’s disease if it weren’t for the inconvenient fact that γ-secretase also helps process the signal transduction molecule Notch. Clearly indispensable in development, the functions of Notch in adults remain poorly defined. A role in thymocyte maturation is known and tied to the toxicity of classic γ-secretase inhibitors (see ARF related news story). What's more, recent experiments have shown that ablating the catalytic core of γ-secretase leads to memory and learning defects in adult mice; these include the dampening of long-term potentiation (LTP), a phenomenon that is integral to the learning process (see ARF related news story). Furukawa’s current work extends this last observation.

First author Yue Wang and colleagues made their discovery while characterizing Notch antisense (NAS) mice. Expressing antisense Notch RNA, these animals are known to have their Notch expression reduced by 50 to 70 percent in hematopoietic cells. When the scientists examined hippocampal cells, they found similar reductions in protein levels. To trace the consequences of this loss, Wang and colleagues measured high frequency stimulation (HFS)-induced activation of NF-kB, a known downstream target in the Notch signaling pathway. Mobility shift assays visualize activation of this transcription factor, and the scientists found that while HFS causes robust mobility shifts of samples from normal mice, NF-kB activation in NAS mice undergoing the same stimulation was negligible.

Does this have physiological consequences? To address this issue, Wang and colleagues compared neurotransmission in hippocampal slices. Basal transmission was similar in wild-type and NAS hippocampal tissue; however, HFS-stimulated increases in postsynaptic potentials, a common measure of LTP, nearly doubled in normal mice but were absent in NAS mice. In addition, low frequency stimulation used to induce the opposite of LTP, long-term depression (LTD), caused much greater reduction in postsynaptic potentials in NAS mice. Taken together, these results suggest that Notch signaling participates in the regulation of LTP and LTD and, by extension, in learning and memory.

As for the potential use of γ-secretase inhibitors for AD, the authors join a growing chorus of scientists when they caution that “efforts to develop γ-secretase inhibitors as therapeutic agents for Alzheimer’s disease, based on their ability to reduce generation of amyloid-β peptide from amyloid precursor protein, may be hampered by the simultaneous inhibition of Notch 1 cleavage.” It is worth noting, though, that some researchers hold out hope that new drugs can be developed that selectively inhibit the amyloid cleavage activity of γ-secretase while leaving Notch cleavage intact (see ARF related news story).—Tom Fagan

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  1. Notch signaling plays a crucial role on cell fate specification during neuronal development in C. elegans, Drosophila and vertebrates. In the adult brain, however, the role of Notch signaling on neuronal morphology and function is largely unknown. Now, Wang et al. used Notch-1 antisense (NAS) transgenic mice expressing reduced levels of Notch-1 to demonstrate that Notch signaling is required for synaptic plasticity in the hippocampus, a brain region classically implicated in the acquisition of new memories. These authors found reduced maintenance of LTP and enhanced LTD in NAS-transgenic mice. Impaired LTP in hippocampal slices from NAS-transgenic mice was associated with reduced CBF1 activation, whereas incubation with the Notch ligand Jagged-1 increased Notch activity and LTP.

    This data linking Notch signaling and synaptic plasticity, together with recent findings from Alcino Silva’s lab (Costa et al., 2003; also see ARF related news story) showing memory deficits in Notch mutant mice, highlight, for the first time, the importance of the Notch signaling pathway for synaptic plasticity and learning and memory.

    These findings may be also relevant for Alzheimer’s disease (AD) because presenilin/γ-secretase facilitates the cleavage and release of the Notch intracellular domain (NICD), which is critical for Notch-mediated gene expression. Interestingly, familial AD mutations in presenilins and loss of PS function impair Notch-1 cleavage, raising the possibility that impaired Notch signaling may contribute to learning and memory deficits in familial AD. Whether mutations in PS may contribute to synaptic and memory impairments by affecting Notch signaling alone or in combination with other mechanisms (i.e., Aβ generation, protein trafficking, etc.) will need to be resolved in the future. While the synaptic and memory mechanisms regulated by presenilins are starting to be revealed, the present study contributes to our understanding of how altered PS activity may lead to cognitive dysfunction in AD.

    References:

    . Learning and memory deficits in Notch mutant mice. Curr Biol. 2003 Aug 5;13(15):1348-54. PubMed.

References

News Citations

  1. New Orleans: Out Go Classic γ-Secretase Inhibitors, In Come More Dexterous NSAIDs?
  2. The Senility-Presenilin Connection Turned Upside Down
  3. St. Moritz, Part 4. (It) Take(s) Five (To Make Aβ), New BACE Mice

Further Reading

Primary Papers

  1. . Involvement of Notch signaling in hippocampal synaptic plasticity. Proc Natl Acad Sci U S A. 2004 Jun 22;101(25):9458-62. PubMed.