Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation.

Authors: Saito T; Iwata N; Tsubuki S; Takaki Y; Takano J; Huang SM; Suemoto T; Higuchi M; Saido TC

Abstract: Expression of somatostatin in the brain declines during aging in various mammals including apes and humans. A prominent decrease in this neuropeptide also represents a pathological characteristic of Alzheimer disease. Using in vitro and in vivo paradigms, we show that somatostatin regulates the metabolism of amyloid beta peptide (Abeta), 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 Abeta, Abeta(42), 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 Abeta 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.

Keywords: Aging; Alzheimer Disease/*metabolism; Amyloid beta-Peptides/*metabolism; Animals; Brain/*metabolism; Cells, Cultured; Hippocampus/metabolism; Humans; Mice; Mice, Knockout; Neprilysin/metabolism; Somatostatin/*pharmacology; Transfection
Journal: Nature medicine
Volume: 11
Issue: 4
Pages: 434-9
Date: March 22, 2005
PMID: 15778722
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Citation:

Saito T, Iwata N, Tsubuki S, Takaki Y, Takano J, Huang SM, Suemoto T, Higuchi M, Saido TC (2005) Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nature medicine 11: 434-9.


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