14 June 2004. 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.
Wang Y, Chan SL, Miele L, Yao PJ, Mackes J, Ingram DK, Mattson MP, Furukawa K. Involvement of Notch signaling in hippocampal synaptic plasticity. PNAS June 2004. Early Edition. Abstract