Somatostatin Receptor Subtype-4 Regulates mRNA Expression of Amyloid-Beta Degrading Enzymes and Microglia Mediators of Phagocytosis in Brains of 3xTg-AD Mice

Sandoval, Karin E.; Umbaugh, David S.; House, Austin; Crider, A. Michael; Witt, K.

doi:10.1007/s11064-019-02890-6

Cited by 18 publications

(17 citation statements)

References 59 publications

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“…Small molecule SST receptor agonists aiming at enhancing the clearance of Aβ through neprilysin activation have been proposed as therapeutic options in AD. However, they were administered either intracerebroventricularly to bypass the BBB 45 , 46 , 78 or as a chronic intraperitoneal administration on daily basis over a period of 28 days 79 . 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.…”

Section: Discussionmentioning

confidence: 99%

“…SST could potentially be used as a therapeutic option in AD through its ability to enhance the activity of neprilysin and thereby reducing the amount of Aβ in the brain. Previous studies have tested small molecule drug agonists of SSTR4 45 , 46 , which activated neprilysin and decreased Aβ. In the current study, we instead use the specific naturally occurring 14 amino acid SST peptide as a therapeutic option to reduce the Aβ brain concentrations through neprilysin activation.…”

Section: Introductionmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Somatostatin is a cyclic neuropeptide, which inhibits the secretion of several excitatory and inhibitory mediators, such as somatotropin, glucagon, insulin, acetylcholine, glutamate and gamma-aminobutyric acid (GABA) [ 1 ]. It regulates a range of physiological functions like sleep, motor activity, sensory functions, emotions, learning and memory, as well as different pathological conditions like pain, inflammation [ 2 , 3 , 4 , 5 ], neurodegeneration [ 6 , 7 , 8 , 9 ], anxiety and depression [ 10 , 11 , 12 , 13 ]. In the central nervous system, there are long protruding and short proximal somatostatin-containing GABAergic interneurons [ 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Human Somatostatin SST4 Receptor Transgenic Mice: Construction and Brain Expression Pattern Characterization

Nemes

Bölcskei

Kecskés

et al. 2021

IJMS

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Somatostatin receptor subtype 4 (SST4) has been shown to mediate analgesic, antidepressant and anti-inflammatory functions without endocrine actions; therefore, it is proposed to be a novel target for drug development. To overcome the species differences of SST4 receptor expression and function between humans and mice, we generated an SST4 humanized mouse line to serve as a translational animal model for preclinical research. A transposon vector containing the hSSTR4 and reporter gene construct driven by the hSSTR4 regulatory elements were created. The vector was randomly inserted in Sstr4-deficient mice. hSSTR4 expression was detected by bioluminescent in vivo imaging of the luciferase reporter predominantly in the brain. RT-qPCR confirmed the expression of the human gene in the brain and various peripheral tissues consistent with the in vivo imaging. RNAscope in situ hybridization revealed the presence of hSSTR4 transcripts in glutamatergic excitatory neurons in the CA1 and CA2 regions of the hippocampus; in the GABAergic interneurons in the granular layer of the olfactory bulb and in both types of neurons in the primary somatosensory cortex, piriform cortex, prelimbic cortex and amygdala. This novel SST4 humanized mouse line might enable us to investigate the differences of human and mouse SST4 receptor expression and function and assess the effects of SST4 receptor agonist drug candidates.

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“…This finding was further validated by a short hairpin RNA (shRNA) library screen [20]. In mouse models of AD, Msr1 deficiency impairs clearance of soluble Aβ and results in increased Aβ deposition and early mortality, whereas pharmacological upregulation of Msr1 leads to enhanced Aβ clearance [20, 21]. Therefore, it is reasonable to speculate that Msr1 could play a scavenger function for a broad range of misfolded protein aggregates including prions.…”

Section: Discussionmentioning

confidence: 99%

“…As an important phagocytic receptor, Msr1 can mediate uptake of fibrillary amyloid β (Aβ) in vitro [18, 19] and Msr1 deficiency in mouse models of AD markedly accelerates Aβ accumulation and disease progression, whereas pharmacological upregulation of Msr1 leads to enhanced Aβ clearance. These results collectively suggest that Msr1 is essential for clearing soluble Aβ [20, 21]. Since both Aβ and prion are extracellular misfolded protein aggregates, they may share similar molecular pathways by which microglia take up and degrade the protein aggregates.…”

Section: Introductionmentioning

confidence: 96%

The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

Chen

Aguzzi

et al. 2020

Preprint

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The progression of prion diseases is accompanied by the accumulation of prions in the brain. Ablation of microglia enhances prion accumulation and accelerates disease progression, suggesting that microglia play a neuroprotective role by clearing prions. However, the mechanisms underlying the phagocytosis and clearance of prion are largely unknown. The macrophage scavenger receptor 1 (Msr1) is an important phagocytic receptor expressed by microglia in the brain, and is involved in the uptake and clearance of soluble amyloid-β. We therefore asked whether Msr1 might play a role in prion clearance, and assessed the scavenger function of Msr1 in prion pathogenesis. We found that Msr1 expression was upregulated in prion-infected mouse brains. However, Msr1 deficiency did not change prion disease progression or lesion patterns. Prion deposition in Msr1 deficient mice was similar to their wild type littermates. In addition, prion-induced neuroinflammation was not affected by Msr1 ablation. We conclude that Msr1 does not play a major role in prion pathogenesis.

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Somatostatin Receptor Subtype-4 Regulates mRNA Expression of Amyloid-Beta Degrading Enzymes and Microglia Mediators of Phagocytosis in Brains of 3xTg-AD Mice

Cited by 18 publications

References 59 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

Human Somatostatin SST4 Receptor Transgenic Mice: Construction and Brain Expression Pattern Characterization

The role of macrophage scavenger receptor 1 (Msr1) in prion pathogenesis

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