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Somatostatin regulates brain amyloid β peptide Aβ42 through modulation of proteolytic degradation

Nature Medicine volume 11, pages 434–439 (2005)Cite this article

Abstract

Expression of somatostatin in the brain declines during aging in various mammals including apes and humans1,2. A prominent decrease in this neuropeptide also represents a pathological characteristic of Alzheimer disease3,4. Using in vitro and in vivo paradigms, we show that somatostatin regulates the metabolism of amyloid β peptide (Aβ), the primary pathogenic agent of Alzheimer disease, in the brain through modulating proteolytic degradation catalyzed by neprilysin. Among various effector candidates, only somatostatin upregulated neprilysin activity in primary cortical neurons. A genetic deficiency of somatostatin altered hippocampal neprilysin activity and localization, and increased the quantity of a hydrophobic 42-mer form of Aβ, Aβ42, in a manner similar to presenilin gene mutations that cause familial Alzheimer disease. These results indicate that the aging-induced downregulation of somatostatin expression may be a trigger for Aβ accumulation leading to late-onset sporadic Alzheimer disease, and suggest that somatostatin receptors may be pharmacological-target candidates for prevention and treatment of Alzheimer disease.

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Figure 1: In vitro screening for a neprilysin activating ligand using primary neurons.
Figure 2: Mechanism of somatostatin action and effect on Aβ clearance in vitro.
Figure 3: Neprilysin activities, Aβ levels and APP metabolism in somatostatin-deficient mouse brains.
Figure 4: Localization of neprilysin immunoreactivity in Sst+/+ and Sst+/− mice.

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Acknowledgements

We thank E. Hosoki, M. Sekiguchi, Y. Matsuba, N. Yamazaki and K. Watanabe for technical assistance and A. Miyawaki for valuable discussions. We express our gratitude to U. Hochgeschwender, Oklahoma Medical Research Foundation for providing SSTP knockout mice and helpful comments. We also thank Takeda Chemical Industries Ltd. and C. Gerard, Harvard Medical School, for providing the monoclonal antibodies to Aβ for ELISA and neprilysin knockout mice, respectively. The research was supported by research grants from RIKEN Brain Science Institute, the Ministry of Education, Culture, Sports, Science and Technology of Japan, and Life Science Foundation (Tokyo).

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Author notes

  1. Takashi Saito and Nobuhisa Iwata: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama, 351-0198, Japan

    Takashi Saito, Nobuhisa Iwata, Satoshi Tsubuki, Yoshie Takaki, Jiro Takano, Shu-Ming Huang, Takahiro Suemoto, Makoto Higuchi & Takaomi C Saido

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Correspondence to Nobuhisa Iwata or Takaomi C Saido.

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Supplementary information

Supplementary Fig. 1

Biochemical fractionation of neocortical tissues from SSTP+/+ and SSTP−/− mice. (PDF 51 kb)

Supplementary Fig. 2

Differential effect of pH on neprilysin-catalyzed degradation of Aβ40 and Aβ42. (PDF 54 kb)

Supplementary Table 1

List of reagents subjected to screening. (PDF 16 kb)

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Saito, T., Iwata, N., Tsubuki, S. et al. Somatostatin regulates brain amyloid β peptide Aβ42 through modulation of proteolytic degradation. Nat Med 11, 434–439 (2005). https://doi.org/10.1038/nm1206

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