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

Watamura, Naoto; Kakiya, Naomasa; Nilsson, Per; Tsubuki, Satoshi; Kamano, Naoko; Takahashi, Mika; Hashimoto, Shoko; Sasaguri, Hiroki; Saito, Takashi; Saido, Takaomi C.

doi:10.1101/2020.10.07.329318

Cited by 3 publications

(2 citation statements)

References 59 publications

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“…As such, the results are easier reconciled with a model of Sst affecting Aβ aggregation directly, consistent with recent biochemical and molecular dynamics simulation studies. This scenario also fits with results from new work documenting a relatively close spatial correlation of Sst and Aβ release sites in various brain regions (52). Future work will need to establish if the combined ablation of the Sst and Cort genes will further enhance the impact on Aβ amyloid deposition.…”

Section: Discussionsupporting

confidence: 83%

Somatostatin slows Aβ plaque deposition in aged APP^NL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

Williams

Yan

Wang

et al. 2022

Preprint

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The molecular underpinnings that govern the endoproteolytic release of the amyloid beta peptide (Abeta) from the amyloid precursor protein (APP) are now quite well understood. The same cannot be said for the events that precipitate the aggregation and amyloid deposition of Abeta in Alzheimer′s disease (AD). The 14-amino-acid cyclic neuroendocrine peptide somatostatin (SST-14) has long been thought of as playing a role, foremost by controlling the expression of the Abeta clearing enzyme neprilysin, and more recently by directly interacting with Abeta oligomers. Missing have been in vivo data in a relevant Abeta amyloidosis model. Here we addressed this shortcoming by crossing AppNL-F/NL-F mice with Sst-deficient mice of identical genetic background to assess if and how the presence of Sst influences key pathological hallmarks of Abeta amyloidosis that develop in AppNL-F/NL-F mice after 10 months of age. Surprisingly, we found that Sst had no influence on whole brain neprilysin transcript, protein or activity levels, an observation that cannot be accounted for by a compensatory upregulation of the Sst paralog, cortistatin (Cort), that we observed in 15-month-old Sst-deficient mice. The absence of Sst did lead to a subtle but significant increase in the density of cortical Abeta amyloid plaques. Follow-on western blot analyses of whole brain extracts indicated that Sst interferes with early steps of Abeta assembly that manifest in Sst null brains through the appearance of SDS-stable smears of 55-150 kDa. As expected, no effect of Sst on tau steady-state levels or its phosphorylation were observed. Results from this study are easier reconciled with an emerging body of data that point toward Sst affecting Abeta amyloid plaque formation through direct interference with Abeta aggregation rather than through its effects on neprilysin expression.

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Section: Discussionsupporting

confidence: 83%

Somatostatin slows Aβ plaque deposition in aged APP^NL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

Williams

Yan

Wang

et al. 2022

Preprint

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“…When we showed that gene therapy utilizing NEP activity attenuated A pathology in APP-transgenic mice [13][14][15] and that the neuropeptide somatostatin regulated neuronal A levels in vitro and in vivo [16][17][18][19] , interest within the academic and pharmaceutical industry fields rose significantly given the prospects of applying pharmacological intervention via the somatostatin-NEP pathway to suppress A pathology [20][21][22][23] and thus inhibit or delay the progression of preclinical AD. This concept was consistent with the aging-dependent reduction and oxidative inactivation of neprilysin, [24][25][26][27] along with the disappearance of somatostatin with aging and in AD 28,29 , all of which would lead to accelerated A deposition.…”

Section: Introductionmentioning

confidence: 99%

Neprilysin-sensitive amyloidogenic Aβ versus IDE-sensitive soluble Aβ: a probable mechanistic cause for sporadic Alzheimer’s disease

Sasaguri

Takamura

Watamura

et al. 2021

Preprint

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Neprilysin (NEP) and insulin-degrading enzyme (IDE) are considered the two major catabolic enzymes that degrade amyloid beta peptide (Abeta), the primary cause of Alzheimer's disease (AD). However, their roles in Abeta metabolism in vivo have never been compared in an impartial and side-by-side manner. Here, we crossbred single App knock-in mice with NEP (Mme) KO mice and with IDE (Ide) KO mice to generate double mutants that were analyzed for their biochemical and Abeta pathology properties. We found that NEP is responsible for the metabolism of amyloidogenic insoluble Abeta whereas IDE affects soluble Abeta. A deficiency of NEP, but not of IDE, augmented the formation of Abeta plaques, dystrophic neurites, and astrocytic and microglial activation, all of which are key pathological events in the development of AD. In addition, a deficiency of NEP had no significant impact on the levels of various neuropeptides (somatostatin, substance P, cholecystokinin, and neuropeptide Y), well known to be in vitro substrates for NEP, presumably because NEP is expressed in secretory vesicles and on the presynaptic membranes of excitatory neurons while most if not all neuropeptides are secreted from inhibitory neurons. This argues against the concern that NEP up-regulation for treatment of preclinical AD would reduce the levels of these neuropeptides. These findings indicate that NEP relatively selectively degrades Abeta in the brain. Whereas familial AD (FAD) is unambiguously caused by an increased anabolism of Abeta, and of Abeta42 and Abeta43 in particular, the anabolism of Abeta appears unaffected before its deposition in the brain that subsequently leads to the onset of sporadic AD (SAD). These observations thus suggest that NEP-sensitive amyloidogenic Abeta likely plays a primary pathogenic role in the etiology of SAD. Our findings are consistent with the aging-dependent decline of NEP expression in human brain and with recent genome-wide association studies (GWAS) indicating that variants of the gene encoding NEP (MME) are associated with the risk of SAD development. Taken together, our results imply that the aging-associated decrease in NEP expression is a primary cause of SAD and could thus be a target for the treatment of preclinical AD once other factors such as apolipoprotein E genotypes have also been considered.

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Novel Treatment for Alzheimer’s Disease: Tapping the Somatostatin-evoked Aβ Catabolism via α-endosulfine-K_ATP Channel Pathway

Varghese,

Digholkar,

Deshpande

et al. 2023

Enzymatic Targets for Drug Discovery Against Alzheimer's Disease

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Alzheimer's disease (AD) is a debilitating neurological disease that is known to worsen as people age. As a chronic illness, it has a negative impact on the health and financial well-being of patients and their families. Despite decades of research into new medications and therapy regimens, the therapeutic choices for these conditions are still limited. Although currently available medications for AD do not prevent or stop disease progression, they are used to treat symptoms and provide brief comfort to patients. The development of medications and other therapy modalities to address the unmet medical need has sparked a surge of interest in understanding the mechanism of AD in recent years. Growing bodies of evidence direct towards the treatment of AD by intercepting the Somatostatin-evoked Aβ catabolism in the brain, via the α-endosulfin- -KATP channel pathway. The latter can be achieved through the repurposing or repositioning of drugs previously approved by the regulatory authorities and indicated in other diseases. With the advent of technology in the healthcare sector, these could be corroborated through various in-silico and in-vitro techniques. This article aims to explore the various aspects of the byzantine α-endosulfine-KATP channel pathway while providing information and future prospects for the development of new therapies to combat AD.

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

Cited by 3 publications

References 59 publications

Somatostatin slows Aβ plaque deposition in aged APP^NL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

Somatostatin slows Aβ plaque deposition in aged APP^NL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

Neprilysin-sensitive amyloidogenic Aβ versus IDE-sensitive soluble Aβ: a probable mechanistic cause for sporadic Alzheimer’s disease

Novel Treatment for Alzheimer’s Disease: Tapping the Somatostatin-evoked Aβ Catabolism via α-endosulfine-K_ATP Channel Pathway

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

Cited by 3 publications

References 59 publications

Somatostatin slows Aβ plaque deposition in aged APPNL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

Somatostatin slows Aβ plaque deposition in aged APPNL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

Neprilysin-sensitive amyloidogenic Aβ versus IDE-sensitive soluble Aβ: a probable mechanistic cause for sporadic Alzheimer’s disease

Novel Treatment for Alzheimer’s Disease: Tapping the Somatostatin-evoked Aβ Catabolism via α-endosulfine-KATP Channel Pathway

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Product

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Somatostatin slows Aβ plaque deposition in aged APP^NL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

Somatostatin slows Aβ plaque deposition in aged APP^NL-F/NL-F mice by blocking Aβ aggregation in a neprilysin-independent manner

Novel Treatment for Alzheimer’s Disease: Tapping the Somatostatin-evoked Aβ Catabolism via α-endosulfine-K_ATP Channel Pathway