Somatostatin receptor subtypes 1 and 4 redundantly regulate neprilysin, the major amyloid-beta degrading enzyme in brain

Nilsson, Per; Sörgjerd, Karin; Kakiya, Naomasa; Sasaguri, Hiroki; Watamura, Naoto; Shimozawa, Makoto; Tsubuki, Satoshi; Zhou, Zhulin; Loera-Valencia, Raúl; Takamura, Risa; Sekiguchi, Masaki; Petrich, Aline; Schulz, Stefan; Saito, Takashi; Winblad, Bengt; Saido, Takaomi C.

doi:10.1101/2020.05.09.085795

Cited by 8 publications

(15 citation statements)

References 37 publications

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“…SST peptide alone without scFv8D3 was not used based on previous studies demonstrating its extremely short half-life of less than three min 48 , 55 and that analogs of SST with longer half-lives have been analyzed to see if they passed the BBB and their uptake in brain was low 56 . Importantly, these analogs of SST have no affinity to the receptor subtype 4 57 - 59 , which has high hippocampal and limited peripheral expression 36 and has been identified as the major regulator of neprilysin activity in the brain 60 . A single injection of SST-scFv8D3 induced a significant increase in the levels of neprilysin in the membrane-bound fraction of the brain (Figure 4 C).…”

Section: Resultsmentioning

confidence: 99%

“…These alternative administration strategies produced limited effects, where one dose gave an effect, but a higher dose caused an increase in Aβ aggregates, limiting their clinical application. In addition, a recent study displayed no Aβ lowering effects of the SSTR4 agonist NNC 26-9110 when administered intraperitoneally to a transgenic mouse model of AD over a period of two weeks 60 . If one compares these results to the significant reduction of Aβ42 with our SST-scFv8D3 protein over a period of only four days, it further demonstrates the potency of our approach.…”

Section: Discussionmentioning

confidence: 97%

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Enhanced neprilysin-mediated degradation of hippocampal Aβ42 with a somatostatin peptide that enters the brain

Rofo¹,

Yılmaz²,

Metzendorf³

et al. 2021

Theranostics

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Background: Aggregation of the amyloid-beta (Aβ) peptide is one of the main neuropathological events in Alzheimer's disease (AD). Neprilysin is the major enzyme degrading Aβ, with its activity enhanced by the neuropeptide somatostatin (SST). SST levels are decreased in the brains of AD patients. The poor delivery of SST over the blood-brain barrier (BBB) and its extremely short half-life of only 3 min limit its therapeutic significance. Methods: We recombinantly fused SST to a BBB transporter binding to the transferrin receptor. Using primary neuronal cultures and neuroblastoma cell lines, the ability of the formed fusion protein to activate neprilysin was studied. SST-scFv8D3 was administered to mice overexpressing the Aβ-precursor protein (AβPP) with the Swedish mutation (APPswe) as a single injection or as a course of three injections over a 72 h period. Levels of neprilysin and Aβ were quantified using an Enzyme-linked immunosorbent assay (ELISA). Distribution of SST-scFv8D3 in the brain, blood and peripheral organs was studied by radiolabeling with iodine-125. Results: The construct, SST-scFv8D3, exhibited 120 times longer half-life than SST alone, reached the brain in high amounts when injected intravenously and significantly increased the brain concentration of neprilysin in APPswe mice. A significant decrease in the levels of membrane-bound Aβ42 was detected in the hippocampus and the adjacent cortical area after only three injections. Conclusion: With intravenous injections of our BBB permeable SST peptide, we were able to significantly increase the levels neprilysin, an effect that was followed by a significant and selective degradation of membrane-bound Aβ42 in the hippocampus. Being that membrane-bound Aβ triggers neuronal toxicity and the hippocampus is the central brain area in the progression of AD, the study has illuminated a new potential treatment paradigm with a promising safety profile targeting only the disease affected areas.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Enhanced neprilysin-mediated degradation of hippocampal Aβ42 with a somatostatin peptide that enters the brain

Rofo¹,

Yılmaz²,

Metzendorf³

et al. 2021

Theranostics

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“…All animal experiments were conducted according to guidelines of the RIKEN Center for Brain Science. Srif KO and Sst4 KO mice were kindly provided by Ute Hochgeschwender, Oklahoma Medical Research Foundation as previously described 11 . Sst1 KO mice were purchased from 20 Jackson laboratory 11 .…”

Section: Animalsmentioning

confidence: 99%

“…Srif KO and Sst4 KO mice were kindly provided by Ute Hochgeschwender, Oklahoma Medical Research Foundation as previously described 11 . Sst1 KO mice were purchased from 20 Jackson laboratory 11 . Mme KO mice were used as negative controls 57 .…”

Section: Animalsmentioning

confidence: 99%

“…We previously showed that somatostatin (SST), a neuropeptide known as a somatotropin-release inhibiting hormone 9 , regulates Aβ42 levels in the brain via the upregulation of NEP activity 10 . In addition, we discovered that, of the five SST receptor (SSTR1-5) subtypes, SSTR1 and SSTR4 redundantly regulate NEP activity and 4 modulate Aβ42 levels in the brain 11,12 . In the present study, we address how NEP activity is regulated in the signaling cascade downstream of SST.…”

Section: Introductionmentioning

confidence: 99%

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α-Endosulfine regulates amyloid β 42 via the modulation of neprilysin activity

Watamura

Kakiya

Nilsson

et al. 2020

Preprint

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The neuropeptide somatostatin (SST) regulates amyloid β peptide (Aβ) catabolism by enhancing neprilysin (NEP)-catalyzed proteolytic degradation. However, the mechanism by which SST regulates NEP activity remains unclear. Here we report the identification by differential proteomics of α-endosulfine (ENSA), an endogenous ligand of the ATP-sensitive potassium (KATP) channel, as a negative regulator of NEP activity downstream of SST signaling. Genetic deficiency of ENSA resulted in enhanced NEP activity and decreased Aβ deposition in the brains of wild-type and Alzheimer’s disease (AD) model mice. Pharmacological intervention to increase the probability of KATP channel opening reduced Aβ deposition in AD model mice. Our findings provide new insights into possible mechanisms to prevent AD.

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Cross-species comparative hippocampal transcriptomics in Alzheimer’s disease

Bastiani

Bellaver

Collar

et al. 2021

Preprint

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Alzheimer's disease (AD) is a multifactorial pathology responsible for most cases of dementia worldwide. Only a small percentage of AD cases are due to autosomal dominant mutations, while the vast majority have a sporadic presentation. Yet, preclinical research studies relied for decades on animal models that overexpress human genes found in AD autosomal dominant patients. Thus, one could argue that these models do not recapitulate sporadic AD. To avoid human gene overexpression artifacts, knock-in (KI) models have been developed, such as the novel hAβ-KI mouse model, which are still in early phases of characterization. We hypothesize that comparisons at the transcriptomic level may elucidate critical similarities and differences between transgenic/KI models and AD patients. Thus, we aimed at comparing the hippocampal transcriptomic profiling of overexpression (5xFAD and APP/PS1) and KI (hAβ-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients. We first evaluated differentially expressed genes (DEGs) and Gene Ontology biological processes (GOBP) overlapping cross-species. After, we explored a network-based strategy to identify master regulators (MR) and the similarities of such elements among models and AD subtypes. A multiple sclerosis (MS) dataset was included to test the molecular specificity of the mouse models to AD. Our analysis revealed that all three mouse models presented more DEGs, GOBP terms and enriched signaling pathways in common with LOAD than with EOAD subjects. Furthermore, semantic similarity of enriched GOBP terms showed mouse model-specific biological alterations, and protein-protein interaction analysis of DEGs identified clusters of genes exclusively shared between hAβ-KI mice and LOAD. Furthermore, we identified 17 transcription factor candidates potentially acting as MR of AD in all three models. Finally, though all mouse models showed transcriptomic similarities to LOAD, hAβ-KI mice presented a remarkable specificity to this AD subtype, which might support the use of the novel hAβ-KI mouse model to advance our understanding of sporadic LOAD.

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Somatostatin receptor subtypes 1 and 4 redundantly regulate neprilysin, the major amyloid-beta degrading enzyme in brain

Cited by 8 publications

References 37 publications

Enhanced neprilysin-mediated degradation of hippocampal Aβ42 with a somatostatin peptide that enters the brain

Enhanced neprilysin-mediated degradation of hippocampal Aβ42 with a somatostatin peptide that enters the brain

α-Endosulfine regulates amyloid β 42 via the modulation of neprilysin activity

Cross-species comparative hippocampal transcriptomics in Alzheimer’s disease

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