Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer’s Disease

Svedružić, Željko M.; Vrbnjak, Katarina; Martinović, Manuel; Miletić, Vedran

doi:10.3390/pharmaceutics13040514

Cited by 13 publications

(27 citation statements)

References 75 publications

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“…Inhibitors of γsecretase, such as Semagacestat and Avagacestat, have not been approved for marketing because the former caused significant adverse reactions such as cognitive decline and decreased ability to perform daily activities, and the latter was ineffective [41]. To avoid the negative effects of overall enzyme inhibition, selective γ-secretase modulators (SGSM) could be developed [42].…”

Section: Beta and Gamma Secretase Inhibitionmentioning

confidence: 99%

The Role of Polyphenols in the Treatment of Alzheimer's Disease: Narrative Review

Alattiya

Tarish

Hashim

et al. 2021

Al-Rafidain J Med Sci

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Many epidemiological studies have suggested that consuming a diet rich in polyphenols can help prevent Alzheimer's disease (AD). Based on well-known in vitro and in vivo models of cerebral Aβ amyloidosis, we examined the data on the effects of various natural polyphenols on the aggregation of amyloid-protein (Aβ). These polyphenols effectively prevent oligomerization and fibril formation of Aβ through differential binding patterns, lowering Aβ oligomer-induced synaptic and neuronal toxicity, according to in vitro investigations. Furthermore, in a transgenic mouse model fed orally with such polyphenolic compounds, soluble Aβ oligomers as well as insoluble Aβ deposits in the brain were significantly reduced. Natural polyphenols exhibit anti-amyloidogenic effects on Aβ, in addition to well-known anti-oxidative and anti-inflammatory activities, according to an updated assessment of the literature, implying their potential as therapeutic and/or preventive agents for AD treatment. To prove polyphenols' efficacy as disease-modifying agents, well-designed clinical trials or preventive treatments using various polyphenols are required.

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Section: Beta and Gamma Secretase Inhibitionmentioning

confidence: 99%

The Role of Polyphenols in the Treatment of Alzheimer's Disease: Narrative Review

Alattiya

Tarish

Hashim

et al. 2021

Al-Rafidain J Med Sci

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“…The structures of S100A9 homodimer [55] in complex with DOPA and cyclen-based compounds (Figure 1) were described by using a combination of ligand docking and all-atom MD simulation [56]. Molecular docking was used for the initial search of the binding sites of those ligands on S100A9 homodimer [57].…”

Section: Ligand Dockingmentioning

confidence: 99%

“…The S100A9 structure used in this study was the average from a set of 10 NMR structures downloaded from the protein data bank, ref PDB: 5I8N [55]. The ligands were hydrogenated and charged at pH 7.2, using the Gasteiger protocol [56]. S100A9 was protonated at pH 7.2 using the AMBER98S force field [57].…”

Section: Ligand Docking Studiesmentioning

confidence: 99%

Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly

Arabuli

Iashchishyn

Romanova

et al. 2021

IJMS

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The amyloid cascade is central for the neurodegeneration disease pathology, including Alzheimer’s and Parkinson’s, and remains the focus of much current research. S100A9 protein drives the amyloid-neuroinflammatory cascade in these diseases. DOPA and cyclen-based compounds were used as amyloid modifiers and inhibitors previously, and DOPA is also used as a precursor of dopamine in Parkinson’s treatment. Here, by using fluorescence titration experiments we showed that five selected ligands: DOPA-D-H-DOPA, DOPA-H-H-DOPA, DOPA-D-H, DOPA-cyclen, and H-E-cyclen, bind to S100A9 with apparent Kd in the sub-micromolar range. Ligand docking and molecular dynamic simulation showed that all compounds bind to S100A9 in more than one binding site and with different ligand mobility and H-bonds involved in each site, which all together is consistent with the apparent binding determined in fluorescence experiments. By using amyloid kinetic analysis, monitored by thioflavin-T fluorescence, and AFM imaging, we found that S100A9 co-aggregation with these compounds does not hinder amyloid formation but leads to morphological changes in the amyloid fibrils, manifested in fibril thickening. Thicker fibrils were not observed upon fibrillation of S100A9 alone and may influence the amyloid tissue propagation and modulate S100A9 amyloid assembly as part of the amyloid-neuroinflammatory cascade in neurodegenerative diseases.

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“…when substrate starts accumulating while the enzyme is still processing its substrate [9,10,17]. We show that the second substrate, different drugs, and different FAD mutations, all target the same sites on the presenilin subunit [8,31,32]. Thus, the binding of the second substrate, like different drugs and FAD mutations, can support the conformational changes that interfere with the processive catalysis and Aβ production [8,20,25,32].…”

Section: Introductionmentioning

confidence: 99%

“…We show that the second substrate, different drugs, and different FAD mutations, all target the same sites on the presenilin subunit [8,31,32]. Thus, the binding of the second substrate, like different drugs and FAD mutations, can support the conformational changes that interfere with the processive catalysis and Aβ production [8,20,25,32]. We show that the presented two-substrate mechanism is consistent with different studies of changes in γ-secretase activity in Alzheimer’s disease.…”

Section: Introductionmentioning

confidence: 99%

Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease

Svedružić

Šendula-Jengić

Ostojić

2022

Preprint

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Significance: pathogenic changes in γ-secretase activity, and its response to different drugs, can be greatly affected by changes in saturation of γ-secretase with its substrate. The molecular mechanism is unclear. Results: multiscale molecular dynamics studies show that saturation of γ-secretase with its substrate can result in parallel binding of different substrate molecules at the docking site and the active site. C-terminal domain of the second substrate can bind at cytosolic end of presenilin subunit while γ-secretase is still processing its first substrate. Such interactions can disrupt dynamic presenilin structures that regulate proteolytic steps. Similar disruptions in dynamic presenilin structures can be produced by different drugs and by different disease-causing mutations. Thus, the presented two-substrate mechanism, can explain toxic inhibition of γ-secretase activity and toxic increase in production of the longer, more hydrophobic, Aβ-proteins. Toxic aggregation between N-terminal domains of the two substrates is controlled by nicastrin ectodomain. Such aggregation is more likely to happen with C99-βCTF-APP than with C83-αCTF-APP substrate, which can explain, why β-secretase path is more pathogenic than α-secretase path. The binding of C99-βCTF-APP substrate to γ-secretase can be controlled by substrate-channeling between nicastrin ectodomain and β-secretase. Conclusions: The presented two-substrate mechanism can explain why different studies consistently show that increase in saturation of γ-secretase with its substrate can support pathogenic changes in different sporadic and familiar cases of the disease. Future drug-development strategies can target different physiological mechanisms that control the balance between cellular levels of γ-secretase activity and the total amyloid metabolism.

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Structural Analysis of the Simultaneous Activation and Inhibition of γ-Secretase Activity in the Development of Drugs for Alzheimer’s Disease

Cited by 13 publications

References 75 publications

The Role of Polyphenols in the Treatment of Alzheimer's Disease: Narrative Review

The Role of Polyphenols in the Treatment of Alzheimer's Disease: Narrative Review

Co-Aggregation of S100A9 with DOPA and Cyclen-Based Compounds Manifested in Amyloid Fibril Thickening without Altering Rates of Self-Assembly

Binding of different substrate molecules at the docking site and the active site of γ-secretase can trigger toxic events in sporadic and familial Alzheimer’s disease

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