Publications by Mitko Dimitrov

The metalloprotease ADAMTS4 generates N-truncated A4-x species and marks oligodendrocytes as a source of amyloidogenic peptides in Alzheimer's disease

Patrick Fraering, Mitko Dimitrov, Hermeto Gerber, Sandra Lehmann

Brain accumulation and aggregation of amyloid- (A) peptides is a critical step in the pathogenesis of Alzheimer's disease (AD). Full-length A peptides (mainly A1-40 and A1-42) are produced through sequential proteolytic cleavage of the amyloid precursor pr ...

SPRINGER2019

Zinc and Copper Differentially Modulate Amyloid Precursor Protein Processing by -Secretase and Amyloid- Peptide Production

Patrick Fraering, Mitko Dimitrov, Hermeto Gerber, Guillermo Miguel Garcia Osuna

Recent evidence suggests involvement of biometal homeostasis in the pathological mechanisms in Alzheimer's disease (AD). For example, increased intracellular copper or zinc has been linked to a reduction in secreted levels of the AD-causing amyloid- peptid ...

Amer Soc Biochemistry Molecular Biology Inc2017

Inhibition of Notch pathway arrests PTEN-deficient advanced prostate cancer by triggering p27-driven cellular senescence

Patrick Fraering, Mitko Dimitrov, Hermeto Gerber, Maria Luna Perciato, Jingjing Chen, Andrea Rinaldi

Activation of NOTCH signalling is associated with advanced prostate cancer and treatment resistance in prostate cancer patients. However, the mechanism that drives NOTCH activation in prostate cancer remains still elusive. Moreover, preclinical evidence of ...

Nature Publishing Group2016

Shedding of neurexin 3 beta ectodomain by ADAM10 releases a soluble fragment that affects the development of newborn neurons

Patrick Fraering, Erika Myrna Borcel Novoa, Giorgio Ulrich, Mitko Dimitrov, Magda Maria Palczynska, Marine Krzisch

Neurexins are transmembrane synaptic cell adhesion molecules involved in the development and maturation of neuronal synapses. In the present study, we report that Nrxn3 beta is processed by the metalloproteases ADAM10, ADAM17, and by the intramembrane-clea ...

Nature Research2016

The adipocyte differentiation protein APMAP is an endogenous suppressor of Aβ production in the brain

Bernard Schneider, Patrick Fraering, Alexandre Matz, Mitko Dimitrov, Sébastien Mosser, Justine Pascual

The deposition of amyloid-beta (Aβ) aggregates in the brain is a major pathological hallmark of Alzheimer's disease (AD). Aβ is generated from the cleavage of C-terminal fragments of the amyloid precursor protein (APP-CTFs) by γ-secretase, an intramembrane ...

Oxford University Press2015

Identification of new Presenilin-1 phosphosites: implication for gamma-secretase activity and A beta production

Marc Moniatte, Patrick Fraering, Blanka Halamoda, Alexandre Matz, Mitko Dimitrov, Romain Hamelin, Sébastien Mosser

An important pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-beta (A) peptides in the brain parenchyma, leading to neuronal death and impaired learning and memory. The protease -secretase is responsible for the intramembrane ...

Wiley-Blackwell2015

Production of active glycosylation-deficient gamma-secretase complex for crystallization studies

Florian Maria Wurm, David Hacker, Patrick Fraering, Mitko Dimitrov, Andres Ricardo Lopez Robles, Hermeto Gerber, Virginie Sandra Braman

Alzheimer's disease (AD)-associated gamma-secretase is a ubiquitously expressed multi-subunit protease complex embedded in the lipid bilayer of cellular compartments including endosomes and the plasma membrane. Although gamma-secretase is of crucial intere ...

Wiley-Blackwell2015

Pharmacological and biochemical assessment of γ-secretase-mediated APP processing involved in Alzheimer's disease

Mitko Dimitrov

EPFL2014

Perturbations of the Straight Transmembrane alpha-Helical Structure of the Amyloid Precursor Protein Affect Its Processing by gamma-Secretase

Thomas Lemmin, Patrick Fraering, Matteo Dal Peraro, Mitko Dimitrov

Background: Amyloid- neurotoxicity depends on the specificity of the proteolytic cleavage of the amyloid precursor protein (APP) transmembrane domain. Results: The APP transmembrane -helix is straight in a biological membrane bilayer. Conclusion: The flexi ...

American Society for Biochemistry and Molecular Biology2014

The Amyloid Precursor Protein Maintains an Ideal&Alpha-Helical Conformation in the Lipid Bilayer

Thomas Lemmin, Patrick Fraering, Matteo Dal Peraro, Mitko Dimitrov

Cell Press2014

Highly efficient production of the Alzheimer's γ-Secretase integral membrane protease complex by a multi-gene stable integration approach

Florian Maria Wurm, David Hacker, Patrick Fraering, Lorène Aeschbach, Mitko Dimitrov, Sowmya Balasubramanian

Inefficient production of membrane-embedded multi-protein complexes by conventional methods has largely prevented the generation of high-resolution structural information and the performance of high-throughput drug discovery screens for this class of prote ...

2013

Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Thomas Lemmin, Patrick Fraering, Freddy Radtke, Rajwinder Lehal, Jemila Houacine, Matteo Dal Peraro, Mitko Dimitrov, Andrzej Jacek Fligier

Pathological amino-acid substitutions in the amyloid precursor protein (APP) and chemical gamma-secretase modulators affect the processing of APP by the gamma-secretase complex and the production of the amyloid-beta peptide A beta 42, the accumulation of w ...

Nature Publishing Group2013

The Role of γ-Secretase Activating Protein (GSAP) and Imatinib in the Regulation of γ-Secretase Activity and Amyloid-β Generation

Patrick Fraering, Mitko Dimitrov, Valérie Eligert

gamma-Secretase is a large enzyme complex comprising presenilin, nicastrin, presenilin enhancer 2, and anterior pharynx-defective 1 that mediates the intramembrane proteolysis of a large number of proteins including amyloid precursor protein and Notch. Rec ...

2013

Intrinsic Transmembrane Flexibility of the Amyloid Precursor Protein Explored by Molecular Simulations

Thomas Lemmin, Patrick Fraering, Matteo Dal Peraro, Mitko Dimitrov

Cell Press2013

Generation of monoclonal antibody fragments binding the native γ-secretase complex for use in structural studies

Patrick Fraering, Lorène Aeschbach, Claude André Schweizer, Mitko Dimitrov

A detailed understanding of γ-secretase structure is crucially needed to elucidate its unique properties of intramembrane protein cleavage and to design therapeutic compounds for the safe treatment of Alzheimer's disease. γ-Secretase is an enzyme complex c ...

Amer Chemical Soc2012

Label-free imaging of cerebral β-amyloidosis with extended-focus optical coherence microscopy

Theo Lasser, Martin Villiger, Corinne Berclaz, Christophe Pache, Patrick Fraering, Tristan Bolmont, Mitko Dimitrov, Arno Pino Bouwens

We demonstrate label-free imaging of cerebral β-amyloidosis ex vivo and in a living mouse model of Alzheimer's disease using extended focus Fourier domain optical coherence microscopy (xfOCM). xfOCM provides 3D, high-resolution images of individual β-amylo ...

Society for Neuroscience2012

Mercury is a direct and potent γ-secretase inhibitor affecting Notch processing and development in Drosophila

Patrick Fraering, Bruno Lemaitre, Mitko Dimitrov, Takayuki Kuraishi, Isabelle Chang

Prenatal exposure to mercury causes neurodevelopmental disorders and neurological pathologies in infants, such as microcephaly and mental retardation. Despite critical importance, the molecular interactions leading to mercury toxicity are yet to be elucida ...

2011