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  1. Article ; Online: New precision medicine avenues to the prevention of Alzheimer's disease from insights into the structure and function of γ-secretases.

    De Strooper, Bart / Karran, Eric

    The EMBO journal

    2024  Volume 43, Issue 6, Page(s) 887–903

    Abstract: Two phase-III clinical trials with anti-amyloid peptide antibodies have met their primary goal, i.e. slowing of Alzheimer's disease (AD) progression. However, antibody therapy may not be the optimal therapeutic modality for AD prevention, as we will ... ...

    Abstract Two phase-III clinical trials with anti-amyloid peptide antibodies have met their primary goal, i.e. slowing of Alzheimer's disease (AD) progression. However, antibody therapy may not be the optimal therapeutic modality for AD prevention, as we will discuss in the context of the earlier small molecules described as "γ-secretase modulators" (GSM). We review here the structure, function, and pathobiology of γ-secretases, with a focus on how mutations in presenilin genes result in early-onset AD. Significant progress has been made in generating compounds that act in a manner opposite to pathogenic presenilin mutations: they stabilize the proteinase-substrate complex, thereby increasing the processivity of substrate cleavage and altering the size spectrum of Aβ peptides produced. We propose the term "γ-secretase allosteric stabilizers" (GSAS) to distinguish these compounds from the rather heterogenous class of GSM. The GSAS represent, in theory, a precision medicine approach to the prevention of amyloid deposition, as they specifically target a discrete aspect in a complex cell biological signalling mechanism that initiates the pathological processes leading to Alzheimer's disease.
    MeSH term(s) Humans ; Alzheimer Disease/genetics ; Alzheimer Disease/prevention & control ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/chemistry ; Amyloid beta-Peptides/genetics ; Precision Medicine ; Presenilins/therapeutic use ; Presenilin-1/genetics ; Amyloid beta-Protein Precursor/genetics
    Chemical Substances Amyloid Precursor Protein Secretases (EC 3.4.-) ; Amyloid beta-Peptides ; Presenilins ; Presenilin-1 ; Amyloid beta-Protein Precursor
    Language English
    Publishing date 2024-02-23
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 586044-1
    ISSN 1460-2075 ; 0261-4189
    ISSN (online) 1460-2075
    ISSN 0261-4189
    DOI 10.1038/s44318-024-00057-w
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Editorial overview: Neurobiology of disease.

    De Strooper, Bart / Zoghbi, Huda

    Current opinion in neurobiology

    2022  Volume 72, Page(s) iv–ix

    Language English
    Publishing date 2022-03-03
    Publishing country England
    Document type Editorial
    ZDB-ID 1078046-4
    ISSN 1873-6882 ; 0959-4388
    ISSN (online) 1873-6882
    ISSN 0959-4388
    DOI 10.1016/j.conb.2022.02.001
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  3. Book: Macro roles for MicroRNAs in the life and death of neurons

    De Strooper, Bart

    2010  

    Title variant Macro-roles for MicroRNAs in the life and death of neurons
    Author's details Bart de Strooper ... (ed.)
    Keywords Nervenzelle ; Small RNA ; Nervendegeneration
    Subject Small RNS ; sRNA ; sRNS ; Neurodegenerative Krankheit ; Neurodegenerative Erkrankung ; Ganglienzelle ; Neurozyt ; Neuron
    Language English
    Size XYII, 121 S. : Ill., 235 mm x 155 mm
    Publisher Springer
    Publishing place Berlin u.a.
    Publishing country Germany
    Document type Book
    HBZ-ID HT016196273
    ISBN 978-3-642-04297-3 ; 9783642042980 ; 3-642-04297-X ; 3642042988
    Database Catalogue ZB MED Medicine, Health

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    Shelf markLoan statusLocation
    2010 A 216 order for loan Magazin

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  4. Article ; Online: The amyloid hypothesis in Alzheimer disease: new insights from new therapeutics.

    Karran, Eric / De Strooper, Bart

    Nature reviews. Drug discovery

    2022  Volume 21, Issue 4, Page(s) 306–318

    Abstract: Many drugs that target amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has ... ...

    Abstract Many drugs that target amyloid-β (Aβ) in Alzheimer disease (AD) have failed to demonstrate clinical efficacy. However, four anti-Aβ antibodies have been shown to mediate the removal of amyloid plaque from brains of patients with AD, and the FDA has recently granted accelerated approval to one of these, aducanumab, using reduction of amyloid plaque as a surrogate end point. The rationale for approval and the extent of the clinical benefit from these antibodies are under intense debate. With the aim of informing this debate, we review clinical trial data for drugs that target Aβ from the perspective of the temporal interplay between the two pathognomonic protein aggregates in AD - Aβ plaques and tau neurofibrillary tangles - and their relationship to cognitive impairment, highlighting differences in drug properties that could affect their clinical performance. On this basis, we propose that Aβ pathology drives tau pathology, that amyloid plaque would need to be reduced to a low level (~20 centiloids) to reveal significant clinical benefit and that there will be a lag between the removal of amyloid and the potential to observe a clinical benefit. We conclude that the speed of amyloid removal from the brain by a potential therapy will be important in demonstrating clinical benefit in the context of a clinical trial.
    MeSH term(s) Alzheimer Disease/pathology ; Amyloid beta-Peptides/metabolism ; Brain/pathology ; Humans ; Neurofibrillary Tangles/metabolism ; Neurofibrillary Tangles/pathology ; Plaque, Amyloid/drug therapy ; Plaque, Amyloid/pathology ; tau Proteins/metabolism
    Chemical Substances Amyloid beta-Peptides ; tau Proteins
    Language English
    Publishing date 2022-02-17
    Publishing country England
    Document type Journal Article ; Review
    ZDB-ID 2062954-0
    ISSN 1474-1784 ; 1474-1776
    ISSN (online) 1474-1784
    ISSN 1474-1776
    DOI 10.1038/s41573-022-00391-w
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  5. Article ; Online: Withdrawal: Functional and topological analysis of Pen-2, the fourth subunit of the γ-secretase complex.

    Bammens, Leen / Chávez-Gutiérrez, Lucía / Tolia, Alexandra / Zwijsen, An / De Strooper, Bart

    The Journal of biological chemistry

    2023  Volume 299, Issue 7, Page(s) 104985

    Language English
    Publishing date 2023-07-04
    Publishing country United States
    Document type Journal Article ; Retraction of Publication
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.104985
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  6. Article ; Online: Diabetes and Alzheimer's disease: shared genetic susceptibility?

    Hardy, John / de Strooper, Bart / Escott-Price, Valentina

    The Lancet. Neurology

    2022  Volume 21, Issue 11, Page(s) 962–964

    MeSH term(s) Humans ; Genetic Predisposition to Disease/genetics ; Alzheimer Disease/genetics ; Genome-Wide Association Study ; Polymorphism, Single Nucleotide ; Diabetes Mellitus/epidemiology ; Diabetes Mellitus/genetics
    Language English
    Publishing date 2022-10-04
    Publishing country England
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 2081241-3
    ISSN 1474-4465 ; 1474-4422
    ISSN (online) 1474-4465
    ISSN 1474-4422
    DOI 10.1016/S1474-4422(22)00395-7
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  7. Article ; Online: Dementia and COVID-19: a health and research funding crisis.

    Aerts, Liesbeth / Lauwers, Elsa / De Strooper, Bart

    The Lancet. Neurology

    2021  Volume 20, Issue 2, Page(s) 90

    MeSH term(s) COVID-19 ; Dementia/epidemiology ; Dementia/therapy ; Humans ; SARS-CoV-2
    Language English
    Publishing date 2021-01-20
    Publishing country England
    Document type Letter ; Comment
    ZDB-ID 2081241-3
    ISSN 1474-4465 ; 1474-4422
    ISSN (online) 1474-4465
    ISSN 1474-4422
    DOI 10.1016/S1474-4422(21)00002-8
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  8. Article ; Online: Neurodegeneration cell per cell.

    Balusu, Sriram / Praschberger, Roman / Lauwers, Elsa / De Strooper, Bart / Verstreken, Patrik

    Neuron

    2023  Volume 111, Issue 6, Page(s) 767–786

    Abstract: The clinical definition of neurodegenerative diseases is based on symptoms that reflect terminal damage of specific brain regions. This is misleading as it tells little about the initial disease processes. Circuitry failures that underlie the clinical ... ...

    Abstract The clinical definition of neurodegenerative diseases is based on symptoms that reflect terminal damage of specific brain regions. This is misleading as it tells little about the initial disease processes. Circuitry failures that underlie the clinical symptomatology are themselves preceded by clinically mostly silent, slowly progressing multicellular processes that trigger or are triggered by the accumulation of abnormally folded proteins such as Aβ, Tau, TDP-43, and α-synuclein, among others. Methodological advances in single-cell omics, combined with complex genetics and novel ways to model complex cellular interactions using induced pluripotent stem (iPS) cells, make it possible to analyze the early cellular phase of neurodegenerative disorders. This will revolutionize the way we study those diseases and will translate into novel diagnostics and cell-specific therapeutic targets, stopping these disorders in their early track before they cause difficult-to-reverse damage to the brain.
    MeSH term(s) Humans ; Alzheimer Disease/metabolism ; alpha-Synuclein/metabolism ; Brain/metabolism ; tau Proteins/metabolism
    Chemical Substances alpha-Synuclein ; tau Proteins
    Language English
    Publishing date 2023-02-13
    Publishing country United States
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't
    ZDB-ID 808167-0
    ISSN 1097-4199 ; 0896-6273
    ISSN (online) 1097-4199
    ISSN 0896-6273
    DOI 10.1016/j.neuron.2023.01.016
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  9. Article ; Online: Functional and topological analysis of PSENEN, the fourth subunit of the γ-secretase complex.

    Serneels, Lutgarde / Bammens, Leen / Zwijsen, An / Tolia, Alexandra / Chávez-Gutiérrez, Lucía / De Strooper, Bart

    The Journal of biological chemistry

    2023  Volume 300, Issue 1, Page(s) 105533

    Abstract: The γ-secretase complexes are intramembrane cleaving proteases involved in the generation of the Aβ peptides in Alzheimer's disease. The complex consists of four subunits, with Presenilin harboring the catalytic site. Here, we study the role of the ... ...

    Abstract The γ-secretase complexes are intramembrane cleaving proteases involved in the generation of the Aβ peptides in Alzheimer's disease. The complex consists of four subunits, with Presenilin harboring the catalytic site. Here, we study the role of the smallest subunit, PSENEN or Presenilin enhancer 2, encoded by the gene Psenen, in vivo and in vitro. We find a profound Notch deficiency phenotype in Psenen
    MeSH term(s) Animals ; Female ; Male ; Mice ; Amyloid Precursor Protein Secretases/genetics ; Amyloid Precursor Protein Secretases/metabolism ; Cell Membrane/metabolism ; Cells, Cultured ; Membrane Proteins/chemistry ; Mice, Inbred C57BL ; Presenilin-1/genetics ; Protein Structure, Tertiary
    Chemical Substances Amyloid Precursor Protein Secretases (EC 3.4.-) ; Membrane Proteins ; Presenilin-1 ; PSENEN protein, human ; presenilin enhancer 2, mouse (EC 3.4.-)
    Language English
    Publishing date 2023-12-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 2997-x
    ISSN 1083-351X ; 0021-9258
    ISSN (online) 1083-351X
    ISSN 0021-9258
    DOI 10.1016/j.jbc.2023.105533
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  10. Article ; Online: Discovery of brain permeable 2-Azabicyclo[2.2.2]octane sulfonamides as a novel class of presenilin-1 selective γ-secretase inhibitors.

    Narlawar, Rajeshwar / Serneels, Lutgarde / Gaffric, Celia / Gijsen, Harrie J M / De Strooper, Bart / Bischoff, François

    European journal of medicinal chemistry

    2023  Volume 260, Page(s) 115725

    Abstract: This paper describes the rational design, synthesis, structure-activity relationship (SAR), and biological profile of presenilin-1 (PSEN-1) complex selective γ-secretase inhibitors, assessed for selectivity using a unique set of four γ-secretase subtype ... ...

    Abstract This paper describes the rational design, synthesis, structure-activity relationship (SAR), and biological profile of presenilin-1 (PSEN-1) complex selective γ-secretase inhibitors, assessed for selectivity using a unique set of four γ-secretase subtype complexes. A set of known PSEN-1 selective γ-Secretase inhibitors (GSIs) was analyzed to understand the pharmacophoric features required for selective inhibition. Conformational modeling suggests that a characteristic 'U' shape orientation between aromatic sulfone/sulfonamide and aryl ring is crucial for PSEN-1 selectivity and potency. Using these insights, a series of brain-penetrant 2-azabicyclo[2,2,2]octane sulfonamides was devised and synthesized as a new class of PSEN-1 selective inhibitors. Compounds 13c and 13k displayed high potency towards PSEN1-APH1B complex but moderate selectivity towards PSEN2 complexes. However, compound (+)-13b displayed low nanomolar potency towards the PSEN1-APH1B complex, little (∼4-fold) selectivity towards PSEN1-APH1A, and high selectivity (>350-fold) versus PSEN2 complexes. Excellent brain penetration, no significant CYP inhibition, or cardiotoxicity, good solubility, and permeability make (+)-13b an excellent candidate for further lead optimization.
    MeSH term(s) Sulfonamides/pharmacology ; Amyloid Precursor Protein Secretases ; Presenilin-1 ; Octanes ; Sulfanilamide ; Brain
    Chemical Substances Sulfonamides ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Presenilin-1 ; octane (X1RV0B2FJV) ; Octanes ; Sulfanilamide (21240MF57M)
    Language English
    Publishing date 2023-08-19
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2023.115725
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