Is Aβ42 regulated by somatostatin through modulation of proteolytic degradation?
Saito, Iwata, and colleagues reported recently that the age-induced down-regulation of somatostatin expression may be triggered by Aβ accumulation by decreasing neprilysin expression (1). Such findings may have important implications for understanding the cellular mechanisms leading to Alzheimer disease and suggest that somatostatin and somatostatin receptors are potential pharmacological targets for preventing and treating the disease. However, they do not fit with the fact that the somatostatin deficit is not correlated with the amyloid load (2,3).
Furthermore, we would like to raise 4 issues concerning the experimental protocols and interpretation of the data.
1. In all their experiments, the authors do not clearly describe the pharmacological treatment used (one or several applications, duration of the treatment). For instance, use of reagents of the supplementary table 1 is concisely explained in Methods, and Fig 2a seems to indicate that somatostatin is added as a single application, at the beginning of a 24-hour experiment, but application of other drugs (agonist, antagonist) is not described in detail.
2. Saito, Iwata, and colleagues check the validity of their activity staining method with 1 μM Thiorphan (a specific inhibitor of neprilysin), but they do not discuss the fact that there is no competition effect of the very high concentration of neprilysin natural subtracts as used in Table 1 (bradykinin, enkephalin, endothelin, neuropeptide Y, substance P, to name a few).
3. The authors show that the somatostatin receptor antagonist BIM 23056 inhibits neprilysin activation. Based on the literature (6) (and as stated in the discussion), sst2 and sst4 receptors are very likely main targets for somatostatin in the cortex and hippocampus. But BIM 23056 is usually considered as a specific antagonist of sst5 receptors and an agonist of sst1 and sst3 receptors 4,5,10,11 (actually, authors present BIM 23056 like a somatostatin receptor antagonist in the article, but like a somatostatin receptor agonist in the legend of Fig. 2).
4. Localization of neprilysin and changes in its subcellular expression in vivo (Fig. 4) are performed by confocal microscopy. However, the resolution of this technique is not entirely appropriate to visualize changes in presynaptic expression, which are usually confirmed by electron microscopy [see, for instance, (12)]. The authors indicate that these observations were confirmed by biochemical fractionation (supplementary Fig. 1). But there are no standard error bars in this figure or any statistical analysis of the differences between somatostatin (+/+) and somatostatin (-/-) mice.
Given these considerations, we would like to point out that the validity of a direct and major role of somatostatin in the regulation of Aβ42 degradation remains subject to caution.
References:
1. Saito T, Iwata N, Tsubuki S, Takaki Y, Takano J, Huang SM, Suemoto T, Higuchi M, Saido TC. Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation.
Nat Med. 2005 Apr;11(4):434-9. Epub 2005 Mar 20. Abstract
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Mol Cell Neurosci. 2001 Apr;17(4):646-61. Abstract
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Br J Pharmacol. 1996 Jun;118(3):445-7. Abstract
12. Buttini M, Masliah E, Barbour R, Grajeda H, Motter R, Johnson-Wood K, Khan K, Seubert P, Freedman S, Schenk D, Games D. Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer's disease.
J Neurosci. 2005 Oct 5;25(40):9096-101. Abstract
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