title: Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation.
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.
authors.affiliation: Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saito
authors.forename: Nobuhisa
authors.initials: N
authors.lastname: Iwata
authors.forename: Satoshi
authors.initials: S
authors.lastname: Tsubuki
authors.forename: Yoshie
authors.initials: Y
authors.lastname: Takaki
authors.forename: Jiro
authors.initials: J
authors.lastname: Takano
authors.forename: Shu-Ming
authors.initials: SM
authors.lastname: Huang
authors.forename: Takahiro
authors.initials: T
authors.lastname: Suemoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Higuchi
authors.forename: Takaomi C
authors.initials: TC
authors.lastname: Saido
mesh_terms: D000375:Aging; D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism*; D002478:Cells, Cultured; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D015260:Neprilysin / Q000378:metabolism; D013004:Somatostatin / Q000494:pharmacology*; D014162:Transfection
chemical_list: D016229:Amyloid beta-Peptides; D013004:Somatostatin; D015260:Neprilysin