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Article ; Online: Evaluation of Virtual Screening Strategies for the Identification of γ-Secretase Inhibitors and Modulators

Alicia Ioppolo / Melissa Eccles / David Groth / Giuseppe Verdile / Mark Agostino

Molecules, Vol 27, Iss 176, p

2022 Volume 176

Abstract: γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis ... ...

Abstract	γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis of substrates has implications in the progression of disease pathologies, including Alzheimer’s disease (AD), cancers, and skin disorders. While several γ-secretase inhibitors have been identified, there has been toxicity observed in clinical trials associated with non-selective enzyme inhibition. To address this, γ-secretase modulators have been identified and pursued as more selective agents. Recent structural evidence has provided an insight into how γ-secretase inhibitors and modulators are recognized by γ-secretase, providing a platform for rational drug design targeting this protease. In this study, docking- and pharmacophore-based screening approaches were evaluated for their ability to identify, from libraries of known inhibitors and modulators with decoys with similar physicochemical properties, γ-secretase inhibitors and modulators. Using these libraries, we defined strategies for identifying both γ-secretase inhibitors and modulators incorporating an initial pharmacophore-based screen followed by a docking-based screen, with each strategy employing distinct γ-secretase structures. Furthermore, known γ-secretase inhibitors and modulators were able to be identified from an external set of bioactive molecules following application of the derived screening strategies. The approaches described herein will inform the discovery of novel small molecules targeting γ-secretase.
Keywords	γ-secretase ; virtual screening ; molecular docking ; pharmacophore model ; Alzheimer’s disease ; Organic chemistry ; QD241-441
Subject code	572 ; 540
Language	English
Publishing date	2022-12-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Evaluation of Virtual Screening Strategies for the Identification of γ-Secretase Inhibitors and Modulators.

Ioppolo, Alicia / Eccles, Melissa / Groth, David / Verdile, Giuseppe / Agostino, Mark

Molecules (Basel, Switzerland)

2021 Volume 27, Issue 1

Abstract	γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis of substrates has implications in the progression of disease pathologies, including Alzheimer's disease (AD), cancers, and skin disorders. While several γ-secretase inhibitors have been identified, there has been toxicity observed in clinical trials associated with non-selective enzyme inhibition. To address this, γ-secretase modulators have been identified and pursued as more selective agents. Recent structural evidence has provided an insight into how γ-secretase inhibitors and modulators are recognized by γ-secretase, providing a platform for rational drug design targeting this protease. In this study, docking- and pharmacophore-based screening approaches were evaluated for their ability to identify, from libraries of known inhibitors and modulators with decoys with similar physicochemical properties, γ-secretase inhibitors and modulators. Using these libraries, we defined strategies for identifying both γ-secretase inhibitors and modulators incorporating an initial pharmacophore-based screen followed by a docking-based screen, with each strategy employing distinct γ-secretase structures. Furthermore, known γ-secretase inhibitors and modulators were able to be identified from an external set of bioactive molecules following application of the derived screening strategies. The approaches described herein will inform the discovery of novel small molecules targeting γ-secretase.
MeSH term(s)	Amyloid Precursor Protein Secretases/antagonists & inhibitors ; Amyloid Precursor Protein Secretases/chemistry ; Drug Discovery/methods ; Gamma Secretase Inhibitors and Modulators/chemistry ; Gamma Secretase Inhibitors and Modulators/pharmacology ; Humans ; Models, Molecular ; Molecular Conformation ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Molecular Structure ; Reproducibility of Results ; Structure-Activity Relationship
Chemical Substances	Gamma Secretase Inhibitors and Modulators ; Amyloid Precursor Protein Secretases (EC 3.4.-)
Language	English
Publishing date	2021-12-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1413402-0
ISSN	1420-3049 ; 1431-5165 ; 1420-3049
ISSN (online)	1420-3049
ISSN	1431-5165 ; 1420-3049
DOI	10.3390/molecules27010176
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Article ; Online: Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer's Disease.

Woodfield, Amy / Gonzales, Tatiana / Helmerhorst, Erik / Laws, Simon / Newsholme, Philip / Porter, Tenielle / Verdile, Giuseppe

International journal of molecular sciences

2022 Volume 23, Issue 24

Abstract: Alzheimer's disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to ... ...

Abstract	Alzheimer's disease (AD) and type 2 diabetes (T2D) are chronic diseases that share several pathological mechanisms, including insulin resistance and impaired insulin signalling. Their shared features have prompted the evaluation of the drugs used to manage diabetes for the treatment of AD. Insulin delivery itself has been utilized, with promising effects, in improving cognition and reducing AD related neuropathology. The most recent clinical trial involving intranasal insulin reported no slowing of cognitive decline; however, several factors may have impacted the trial outcomes. Long-acting and rapid-acting insulin analogues have also been evaluated within the context of AD with a lack of consistent outcomes. This narrative review provided insight into how targeting insulin signalling in the brain has potential as a therapeutic target for AD and provided a detailed update on the efficacy of insulin, its analogues and the outcomes of human clinical trials. We also discussed the current evidence that warrants the further investigation of the use of the mimetics of insulin for AD. These small molecules may provide a modifiable alternative to insulin, aiding in developing drugs that selectively target insulin signalling in the brain with the aim to attenuate cognitive dysfunction and AD pathologies.
Language	English
Publishing date	2022-12-13
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms232415811
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Article ; Online: Quantitative comparison of presenilin protein expression reveals greater activity of PS2-γ-secretase.

Eccles, Melissa K / Main, Nathan / Carlessi, Rodrigo / Armstrong, Ayeisha Milligan / Sabale, Miheer / Roberts-Mok, Brigid / Tirnitz-Parker, Janina E E / Agostino, Mark / Groth, David / Fraser, Paul E / Verdile, Giuseppe

FASEB journal : official publication of the Federation of American Societies for Experimental Biology

2024 Volume 38, Issue 1, Page(s) e23396

Abstract: γ-secretase processing of amyloid precursor protein (APP) has long been of interest in the pathological progression of Alzheimer's disease (AD) due to its role in the generation of amyloid-β. The catalytic component of the enzyme is the presenilins of ... ...

Abstract	γ-secretase processing of amyloid precursor protein (APP) has long been of interest in the pathological progression of Alzheimer's disease (AD) due to its role in the generation of amyloid-β. The catalytic component of the enzyme is the presenilins of which there are two homologues, Presenilin-1 (PS1) and Presenilin-2 (PS2). The field has focussed on the PS1 form of this enzyme, as it is typically considered the more active at APP processing. However, much of this work has been completed without appropriate consideration of the specific levels of protein expression of PS1 and PS2. We propose that expression is an important factor in PS1- and PS2-γ-secretase activity, and that when this is considered, PS1 does not have greater activity than PS2. We developed and validated tools for quantitative assessment of PS1 and PS2 protein expression levels to enable the direct comparison of PS in exogenous and endogenous expression systems, in HEK-293 PS1 and/or PS2 knockout cells. We show that exogenous expression of Myc-PS1-NTF is 5.5-times higher than Myc-PS2-NTF. Quantitating endogenous PS protein levels, using a novel PS1/2 fusion standard we developed, showed similar results. When the marked difference in PS1 and PS2 protein levels is considered, we show that compared to PS1-γ-secretase, PS2-γ-secretase has equal or more activity on APP and Notch1. This study has implications for understanding the PS1- and PS2-specific contributions to substrate processing, and their potential influence in AD pathogenesis.
MeSH term(s)	Humans ; Alzheimer Disease/genetics ; Amyloid beta-Peptides/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Endopeptidases/metabolism ; HEK293 Cells ; Presenilin-1/genetics ; Presenilin-1/metabolism ; Presenilin-2/genetics ; Presenilin-2/metabolism
Chemical Substances	Amyloid beta-Peptides ; Amyloid beta-Protein Precursor ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Endopeptidases (EC 3.4.-) ; Presenilin-1 ; Presenilin-2 ; PSEN2 protein, human
Language	English
Publishing date	2024-01-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	639186-2
ISSN	1530-6860 ; 0892-6638
ISSN (online)	1530-6860
ISSN	0892-6638
DOI	10.1096/fj.202300954RR
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Zs.MO 296: Show issues

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Article: Mitoprotective Effects of a Synergistic Nutraceutical Combination: Basis for a Prevention Strategy Against Alzheimer's Disease.

Jayatunga, Dona P W / Hone, Eugene / Fernando, W M A D Binosha / Garg, Manohar L / Verdile, Giuseppe / Martins, Ralph N

Frontiers in aging neuroscience

2022 Volume 13, Page(s) 781468

Abstract: Evidence to date suggests the consumption of food rich in bioactive compounds, such as polyphenols, flavonoids, omega-3 fatty acids may potentially minimize age-related cognitive decline. For neurodegenerative diseases, such as Alzheimer's disease (AD), ... ...

Abstract	Evidence to date suggests the consumption of food rich in bioactive compounds, such as polyphenols, flavonoids, omega-3 fatty acids may potentially minimize age-related cognitive decline. For neurodegenerative diseases, such as Alzheimer's disease (AD), which do not yet have definitive treatments, the focus has shifted toward using alternative approaches, including prevention strategies rather than disease reversal. In this aspect, certain nutraceuticals have become promising compounds due to their neuroprotective properties. Moreover, the multifaceted AD pathophysiology encourages the use of multiple bioactive components that may be synergistic in their protective roles when combined. The objective of the present study was to determine mechanisms of action underlying the inhibition of Aβ
Language	English
Publishing date	2022-02-21
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2021.781468
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Article: A Synergistic Combination of DHA, Luteolin, and Urolithin A Against Alzheimer's Disease.

Jayatunga, Dona P W / Hone, Eugene / Fernando, W M A D Binosha / Garg, Manohar L / Verdile, Giuseppe / Martins, Ralph N

Frontiers in aging neuroscience

2022 Volume 14, Page(s) 780602

Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. The classical AD brain is characterized by extracellular deposition of amyloid-β (Aβ) protein aggregates as senile plaques and ... ...

Abstract	Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. The classical AD brain is characterized by extracellular deposition of amyloid-β (Aβ) protein aggregates as senile plaques and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated forms of the microtubule-associated protein Tau. There has been limited success in clinical trials for some proposed therapies for AD, so attention has been drawn toward using alternative approaches, including prevention strategies. As a result, nutraceuticals have become attractive compounds for their potential neuroprotective capabilities. The objective of the present study was to derive a synergistic nutraceutical combination
Language	English
Publishing date	2022-02-16
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2022.780602
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Article ; Online: Amla Therapy as a Potential Modulator of Alzheimer's Disease Risk Factors and Physiological Change.

Teimouri, Elham / Rainey-Smith, Stephanie R / Bharadwaj, Prashant / Verdile, Giuseppe / Martins, Ralph N

Journal of Alzheimer's disease : JAD

2020 Volume 74, Issue 3, Page(s) 713–733

Abstract: There is currently no effective treatment for Alzheimer's disease (AD), the most common form of dementia. It has been proposed, however, that a modest delay in onset can significantly reduce the number of cases. Thus, prevention and intervention ... ...

Abstract	There is currently no effective treatment for Alzheimer's disease (AD), the most common form of dementia. It has been proposed, however, that a modest delay in onset can significantly reduce the number of cases. Thus, prevention and intervention strategies are currently the focus of much research. In the search for compounds that potentially confer benefit, the Amla fruit and its extracts have drawn attention. Amla preparations have been used for centuries in traditional Indian medicine systems such as Ayurveda, with various parts of the plant used to treat a variety of diseases. Here we review many animal-based studies, and some clinical trials, which have shown that Amla, and its extracts, exert many positive effects on dyslipidemia, hyperglycemia, inflammation, oxidative stress, apoptosis, and autophagy, that contribute to AD risk. Collectively, this evidence suggests that Amla may be of value as part of an effective disease-delaying treatment for AD.
MeSH term(s)	Alzheimer Disease/physiopathology ; Alzheimer Disease/prevention & control ; Animals ; Antioxidants ; Disease Progression ; Humans ; Phyllanthus emblica ; Phytotherapy/methods ; Plant Extracts/therapeutic use ; Risk Factors
Chemical Substances	Antioxidants ; Plant Extracts
Language	English
Publishing date	2020-02-24
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-191033
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Article ; Online: Are Heat Shock Proteins an Important Link between Type 2 Diabetes and Alzheimer Disease?

Rowles, Joanne Elizabeth / Keane, Kevin Noel / Gomes Heck, Thiago / Cruzat, Vinicius / Verdile, Giuseppe / Newsholme, Philip

International journal of molecular sciences

2020 Volume 21, Issue 21

Abstract: Type 2 diabetes (T2D) and Alzheimer's disease (AD) are growing in prevalence worldwide. The development of T2D increases the risk of AD disease, while AD patients can show glucose imbalance due to an increased insulin resistance. T2D and AD share similar ...

Abstract	Type 2 diabetes (T2D) and Alzheimer's disease (AD) are growing in prevalence worldwide. The development of T2D increases the risk of AD disease, while AD patients can show glucose imbalance due to an increased insulin resistance. T2D and AD share similar pathological features and underlying mechanisms, including the deposition of amyloidogenic peptides in pancreatic islets (i.e., islet amyloid polypeptide; IAPP) and brain (β-Amyloid; Aβ). Both IAPP and Aβ can undergo misfolding and aggregation and accumulate in the extracellular space of their respective tissues of origin. As a main response to protein misfolding, there is evidence of the role of heat shock proteins (HSPs) in moderating T2D and AD. HSPs play a pivotal role in cell homeostasis by providing cytoprotection during acute and chronic metabolic stresses. In T2D and AD, intracellular HSP (iHSP) levels are reduced, potentially due to the ability of the cell to export HSPs to the extracellular space (eHSP). The increase in eHSPs can contribute to oxidative damage and is associated with various pro-inflammatory pathways in T2D and AD. Here, we review the role of HSP in moderating T2D and AD, as well as propose that these chaperone proteins are an important link in the relationship between T2D and AD.
MeSH term(s)	Alzheimer Disease/complications ; Alzheimer Disease/metabolism ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Blood Glucose/metabolism ; Diabetes Mellitus, Type 2/complications ; Diabetes Mellitus, Type 2/metabolism ; Extracellular Space/metabolism ; HSP72 Heat-Shock Proteins/metabolism ; Heat-Shock Proteins/metabolism ; Humans ; Inflammation ; Models, Biological ; Molecular Chaperones/metabolism ; Protein Binding ; Protein Folding ; tau Proteins/metabolism
Chemical Substances	APP protein, human ; Amyloid beta-Protein Precursor ; Blood Glucose ; HSP72 Heat-Shock Proteins ; Heat-Shock Proteins ; MAPT protein, human ; Molecular Chaperones ; tau Proteins
Keywords	covid19
Language	English
Publishing date	2020-11-02
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21218204
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Article ; Online: Targeting Mitophagy in Alzheimer's Disease.

Jayatunga, Dona P W / Hone, Eugene / Bharadwaj, Prashant / Garg, Manohar / Verdile, Giuseppe / Guillemin, Gilles J / Martins, Ralph N

Journal of Alzheimer's disease : JAD

2020 Volume 78, Issue 4, Page(s) 1273–1297

Abstract: Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell survival and death. Maintaining viable populations of mitochondria is therefore ... ...

Abstract	Mitochondria perform many essential cellular functions including energy production, calcium homeostasis, transduction of metabolic and stress signals, and mediating cell survival and death. Maintaining viable populations of mitochondria is therefore critical for normal cell function. The selective disposal of damaged mitochondria, by a pathway known as mitophagy, plays a key role in preserving mitochondrial integrity and quality. Mitophagy reduces the formation of reactive oxygen species and is considered as a protective cellular process. Mitochondrial dysfunction and deficits of mitophagy have important roles in aging and especially in neurodegenerative disorders such as Alzheimer's disease (AD). Targeting mitophagy pathways has been suggested to have potential therapeutic effects against AD. In this review, we aim to briefly discuss the emerging concepts on mitophagy, molecular regulation of the mitophagy process, current mitophagy detection methods, and mitophagy dysfunction in AD. Finally, we will also briefly examine the stimulation of mitophagy as an approach for attenuating neurodegeneration in AD.
MeSH term(s)	Alzheimer Disease/metabolism ; Alzheimer Disease/physiopathology ; Animals ; Humans ; Mitochondria/metabolism ; Mitophagy/physiology
Language	English
Publishing date	2020-12-05
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-191258
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Article ; Online: The role of type 2 diabetes in neurodegeneration.

Verdile, Giuseppe / Fuller, Stephanie J / Martins, Ralph N

Neurobiology of disease

2015 Volume 84, Page(s) 22–38

Abstract: A growing body of evidence links type-2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised neuropathologically by the accumulation of extracellular ... ...

Abstract	A growing body of evidence links type-2 diabetes (T2D) with dementia and neurodegenerative diseases such as Alzheimer's disease (AD). AD is the most common form of dementia and is characterised neuropathologically by the accumulation of extracellular beta amyloid (Aβ) peptide aggregates and intracellular hyper-phosphorylated tau protein, which are thought to drive and/or accelerate inflammatory and oxidative stress processes leading to neurodegeneration. Although the precise mechanism remains unclear, T2D can exacerbate these neurodegenerative processes. Brain atrophy, reduced cerebral glucose metabolism and CNS insulin resistance are features of both AD and T2D. Cell culture and animal studies have indicated that the early accumulation of Aβ may play a role in CNS insulin resistance and impaired insulin signalling. From the viewpoint of insulin resistance and impaired insulin signalling in the brain, these are also believed to initiate other aspects of brain injury, including inflammatory and oxidative stress processes. Here we review the clinical and experimental pieces of evidence that link these two chronic diseases of ageing, and discuss underlying mechanisms. The evaluation of treatments for the management of diabetes in preclinical, and clinical studies and trials for AD will also be discussed.
MeSH term(s)	Animals ; Brain/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Humans ; Neurodegenerative Diseases/metabolism
Language	English
Publishing date	2015-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1211786-9
ISSN	1095-953X ; 0969-9961
ISSN (online)	1095-953X
ISSN	0969-9961
DOI	10.1016/j.nbd.2015.04.008
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