Harrie J. M. Gijsen

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The mechanisms by which mutations in the presenilins (PSEN) or the amyloid precursor protein (APP) genes cause familial Alzheimer disease (FAD) are controversial. FAD mutations increase the release of amyloid β (Aβ)42 relative to Aβ40 by an unknown, possibly gain-of-toxic-function, mechanism. However, many PSEN mutations paradoxically impair γ-secretase and(More)
The TRPA1 channel is activated by a number of pungent chemicals, such as allylisothiocyanate, present in mustard oil and thiosulfinates present in garlic. Most of the known activating compounds contain reactive, electrophilic chemical groups, reacting with cysteine residues in the active site of the TRPA1 channel. This covalent modification results in(More)
ApoE4 is the most important genetic risk factor for Alzheimer’s disease (AD) (1), and we therefore read with great interest the paper by Cramer et al. (2) demonstrating spectacular results of bexarotene on b-amyloid (Ab) accumulation in the brain of mouse models for AD. Bexarotene is a retinoid X receptor (RXR) agonist and approved by the U.S. Food and Drug(More)
Presenilin (PSEN) pathogenic mutations cause familial Alzheimer's disease (AD [FAD]) in an autosomal-dominant manner. The extent to which the healthy and diseased alleles influence each other to cause neurodegeneration remains unclear. In this study, we assessed γ-secretase activity in brain samples from 15 nondemented subjects, 22 FAD patients harboring(More)
The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1(More)
γ-Secretase modulators (GSMs) inhibit the generation of amyloidogenic Aβ42 peptides and are promising agents for treatment or prevention of Alzheimer's disease (AD). Recently, a second generation of GSMs with favorable pharmacological properties has emerged, but preclinical studies to assess their efficacy in vivo are lacking. Such studies rely on(More)
The microtubule associated protein tau causes primary and secondary tauopathies by unknown molecular mechanisms. Post-translational O-GlcNAc-ylation of brain proteins was demonstrated here to be beneficial for Tau.P301L mice by pharmacological inhibition of O-GlcNAc-ase. Chronic treatment of ageing Tau.P301L mice mitigated their loss in body-weight and(More)
Gamma-secretase, a membrane bound protease which cleaves the transmembrane protein amyloid-β protein precursor (AβPP), is a therapeutic target for Alzheimer's disease. Gamma-secretase inhibitors (GSIs) and modulators (GSMs) are being investigated as potential disease-modifying agents. Preclinical in vivo models to monitor the activity on gamma-secretase are(More)
The TRPA1 channel can be considered as a key biological sensor to irritant chemicals. In this paper, the discovery of 11H-dibenz[b,e]azepines (morphanthridines) and dibenz[b,f][1,4]oxazepines is described as extremely potent agonists of the TRPA1 receptor. This has led to the discovery that most of the known tear gases are potent TRPA1 activators. The(More)