Somatostatin regulates brain amyloid β peptide Aβ42 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.

Elucidating the Role of Disulfide Bond on Amyloid Formation and Fibril Reversibility of Somatostatin-14

“…Somatostatin-14 (SST- 14) 4 is a small cyclic peptide hormone secreted by hypothalamus, one of the well known functions of which is to inhibit the release of growth hormone (16). Other important functions of somatostatin-14 include inhibition of gastrin and gastric acid secretion, inhibition of insulin and glucagon secretion in pancreas, and regulation of amyloid-␤ peptide, A␤42, in brain (17)(18)(19) Somatostatin-14 has previously been reported to form amyloid fibrils in vitro (4,20). In this study, we first show that somatostatin-14 is stored as amyloid-like aggregates in rat hypothalamus tissues (Fig.…”

Somatostatin and Alzheimer's disease

“…This effect is clearly mediated via SRIF receptors since both an SSTR antagonist (BIM23056) and a Gi inhibitor (pertussis toxin) inhibit neprilysin activation. Thirdly, in the hippocampus of SRIF-precursor protein-knockout mice, neprilysin activity was found to be significantly lower than that in wild-type mice (Saito et al, 2005). In addition, a 50% increase in A1-42 levels was (Figure 1), thus leading to late-onset sporadic AD.…”

“…First, both neprilysin expression and SRIF content in the brain decrease during aging. Secondly, in primary cortical neurons, Saito et al (2005) have demonstrated that SRIF significantly increases neuronal neprilysin activity and decreases A1-42 levels in the culture medium. This effect is clearly mediated via SRIF receptors since both an SSTR antagonist (BIM23056) and a Gi inhibitor (pertussis toxin) inhibit neprilysin activation.…”

Therapeutic Potential of Amyloid β-Degrading Enzymes in Alzheimer‘s Disease

“…During aging, NEP and IDE levels are selectively reduced in vulnerable regions of the brain, such as the hippocampus, where the Aβ appears to be readily deposited first, but not in the cerebellum and striatum, where no significant Aβ accumulation occurs [38,39]. The aging-induced reduction of NEP levels has been attributed, at least partially, to age-dependent depletion of somatostatin, which stimulates NEP expression [40]. In AD brains, NEP levels were significantly lower in regions with high levels of plaque, such as the hippocampus and temporal gyrus [41], further supporting the notion that the deficiency in NEP or IDE might contribute to region-specific Aβ accumulation in sporadic AD.…”

“…For example, somatostatin significantly elevated neuronal NEP activity, probably by affecting protein turnover and cellular localization [40]. Agonists for somatostatin receptors might be used to augment the Aβ-degrading activities of NEPs [40].…”