Physiological and pathological roles of the γ-secretase complex

Carroll, Courtney M.; Li, Yueming

doi:10.1016/j.brainresbull.2016.04.019

Cited by 43 publications

(37 citation statements)

References 134 publications

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“…Nicastrin, presenilin enhancer 2 and anterior pharynx-defective 1 are critical components of γ-secretase and may modulate enzyme activity in response to physiological stimuli [22][23][24] . This unique cleavage process of APP provides essential targets for AD therapeutics [25] .…”

Section: Structure Of the Amyloid Beta Peptidementioning

confidence: 99%

“…Approximately 25% of the surface is uninterruptedly hydrophobic, and the compact coil structure is meta-stable, which may lead to a global conformational rearrangement and the formation of an intermolecular beta-sheet secondary structure caused by fibrillization. The 3D NMR structures of Aβ peptide (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25) and Aβ peptide (28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38) show two helical regions connected by a regular type I β-turn. Aβ peptide (25-35) is a highly toxic synthetic derivative of Aβ peptides.…”

Section: Aβ Monomermentioning

confidence: 99%

“…Aβ peptide (25-35) is a highly toxic synthetic derivative of Aβ peptides. Researchers have used NMR and CD investigation of Aβ peptide (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) and fluoro-alcohols to scan its conformational properties. The peptide behaves as a typical transmembrane helix in a lipidic environment, forming fibrillar aggregates, which suggests a direct mechanism of neurotoxicity [30,31] .…”

Section: Aβ Monomermentioning

confidence: 99%

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Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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Amyloid beta peptide (Aβ) is produced through the proteolytic processing of a transmembrane protein, amyloid precursor protein (APP), by β-and γ-secretases. Aβ accumulation in the brain is proposed to be an early toxic event in the pathogenesis of Alzheimer's disease, which is the most common form of dementia associated with plaques and tangles in the brain. Currently, it is unclear what the physiological and pathological forms of Aβ are and by what mechanism Aβ causes dementia. Moreover, there are no efficient drugs to stop or reverse the progression of Alzheimer's disease. In this paper, we review the structures, biological functions, and neurotoxicity role of Aβ. We also discuss the potential receptors that interact with Aβ and mediate Aβ intake, clearance, and metabolism. Additionally, we summarize the therapeutic developments and recent advances of different strategies for treating Alzheimer's disease. Finally, we will report on the progress in searching for novel, potentially effective agents as well as selected promising strategies for the treatment of Alzheimer's disease. These prospects include agents acting on Aβ, its receptors and tau protein, such as small molecules, vaccines and antibodies against Aβ; inhibitors or modulators of β-and γ-secretase; Aβ-degrading proteases; tau protein inhibitors and vaccines; amyloid dyes and microRNAs.

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Section: Structure Of the Amyloid Beta Peptidementioning

confidence: 99%

Section: Aβ Monomermentioning

confidence: 99%

Section: Aβ Monomermentioning

confidence: 99%

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Amyloid beta: structure, biology and structure-based therapeutic development

et al. 2017

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“…Aβ is generated as the result of the sequential cleavage of amyloid precursor protein (APP) by β-site amyloid precursor protein cleaving enzyme 1 (BACE1) and γ-secretase [45, 394]. The cleavage position of the γ-secretase in the transmembrane domain of APP is imprecise, resulting in the production of Aβ peptides of variable length [166, 289].…”

Section: Aβ Pathologymentioning

confidence: 99%

Current state of Alzheimer’s fluid biomarkers

et al. 2018

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Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a complex and heterogeneous pathophysiology. The number of people living with AD is predicted to increase; however, there are no disease-modifying therapies currently available and none have been successful in late-stage clinical trials. Fluid biomarkers measured in cerebrospinal fluid (CSF) or blood hold promise for enabling more effective drug development and establishing a more personalized medicine approach for AD diagnosis and treatment. Biomarkers used in drug development programmes should be qualified for a specific context of use (COU). These COUs include, but are not limited to, subject/patient selection, assessment of disease state and/or prognosis, assessment of mechanism of action, dose optimization, drug response monitoring, efficacy maximization, and toxicity/adverse reactions identification and minimization. The core AD CSF biomarkers Aβ42, t-tau, and p-tau are recognized by research guidelines for their diagnostic utility and are being considered for qualification for subject selection in clinical trials. However, there is a need to better understand their potential for other COUs, as well as identify additional fluid biomarkers reflecting other aspects of AD pathophysiology. Several novel fluid biomarkers have been proposed, but their role in AD pathology and their use as AD biomarkers have yet to be validated. In this review, we summarize some of the pathological mechanisms implicated in the sporadic AD and highlight the data for several established and novel fluid biomarkers (including BACE1, TREM2, YKL-40, IP-10, neurogranin, SNAP-25, synaptotagmin, α-synuclein, TDP-43, ferritin, VILIP-1, and NF-L) associated with each mechanism. We discuss the potential COUs for each biomarker.

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“…This proteolytic activity presents several peculiar properties that have made its molecular identification and its precise mode of action rather challenging. Firstly, in contrary to the monomeric type‐I transmembrane α‐ and β‐secretases, the γ‐secretase constitutes a heterotetrameric complex that is composed of PS1 or PS2, NCT, APH‐1, and PEN‐2 (Figure C) . Secondly, the γ‐secretase presents the remarkable ability to cleave peptide bonds within the lipid bilayer of the membrane whereby a highly hydrophobic environment is not a priority in being conducive for hydrolysis.…”

Section: Secretase Familiesmentioning

confidence: 99%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

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Physiological and pathological roles of the γ-secretase complex

Cited by 43 publications

References 134 publications

Amyloid beta: structure, biology and structure-based therapeutic development

Amyloid beta: structure, biology and structure-based therapeutic development

Current state of Alzheimer’s fluid biomarkers

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

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