A5064101099- Alzheimer's disease research and treatments
- Glycosylation and Glycoproteins Research
- Neuroinflammation and Neurodegeneration Mechanisms
- S100 Proteins and Annexins
- Cholinesterase and Neurodegenerative Diseases
- Neuroscience and Neuropharmacology Research
- Carbohydrate Chemistry and Synthesis
- Prion Diseases and Protein Misfolding
- Dementia and Cognitive Impairment Research
- Monoclonal and Polyclonal Antibodies Research
- Functional Brain Connectivity Studies
- Neuropeptides and Animal Physiology
- Renin-Angiotensin System Studies
- Lipid Membrane Structure and Behavior
- Lysosomal Storage Disorders Research
- Nicotinic Acetylcholine Receptors Study
- Galectins and Cancer Biology
- Integrated Circuits and Semiconductor Failure Analysis
- Signaling Pathways in Disease
- Advanced Proteomics Techniques and Applications
- Electron and X-Ray Spectroscopy Techniques
- Advanced Electron Microscopy Techniques and Applications
- Computational Drug Discovery Methods
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Protein Kinase Regulation and GTPase Signaling
Janssen (Belgium)
2018-2023
KU Leuven
2011-2016
Leiden University Medical Center
2015
Institute of Pathology and Genetics
2013
Abstract Cerebrospinal fluid (CSF) p-tau181 (tau phosphorylated at threonine 181) is an established biomarker of Alzheimer’s disease (AD), reflecting abnormal tau metabolism in the brain. Here we investigate performance CSF p-tau217 as a AD comparison to p-tau181. In Swedish BioFINDER cohort ( n = 194), shows stronger correlations with positron emission tomography (PET) tracer [ 18 F]flortaucipir, and more accurately identifies individuals abnormally increased F]flortaucipir retention....
Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decline synaptic dysfunction, leading to neurodegeneration in vulnerable brain regions Alzheimer's disease. The unmet need effective therapy for disease, combined problematic pharmacological approaches, led the field explore immunotherapy, first against amyloid peptides recently Tau. Here we adapted liposome-based vaccine that proved safe efficacious, incorporated a synthetic phosphorylated peptide...
Neuroinflammation and microglial activation are significant processes in Alzheimer's disease pathology. Recent genome-wide association studies have highlighted multiple immune-related genes with disease, experimental data demonstrated proliferation as a component of the neuropathology. In this study, we tested efficacy selective CSF1R inhibitor JNJ-40346527 (JNJ-527) P301S mouse tauopathy model. We first anti-proliferative effects JNJ-527 on microglia ME7 prion model, its impact inflammatory...
Pituitary adenylate cyclase-activating polypeptide (PACAP) has neuroprotective and neurotrophic properties is a potent α-secretase activator. As PACAP peptides their specific receptor PAC1 are localized in central nervous system areas affected by Alzheimer's disease (AD), this study aims to examine the role of natural peptide as valuable approach AD therapy. We investigated effect brain an transgenic mouse model. The long-term intranasal daily application stimulated nonamyloidogenic...
Summary When electron microscopy (EM) was introduced in the 1930s it gave scientists their first look into nanoworld of cells. Over last 80 years EM has vastly increased our understanding complex cellular structures that underlie diverse functions cells need to maintain life. One drawback been difficult overcome inherent lack volume information, mainly due limit on thickness sections could be viewed a transmission microscope (TEM). For many struggled achieve three‐dimensional (3D) using...
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 pharmacological inhibition O-GlcNAc-ase. Chronic treatment ageing mitigated their loss in body-weight improved motor deficits, while the survival 3-fold higher at pre-fixed study endpoint age 9.5 months. Moreover, O-GlcNAc-ase significantly breathing parameters mice,...
Abstract Introduction Diagnosis of Alzheimer's disease (AD) based on amyloid beta (A), pathologic tau (T), and neurodegeneration (N) biomarkers in peripheral fluids promises to accelerate clinical trials intercept earlier. Methods Qualification a Simoa plasma p217+tau assay was performed, followed by utility evaluation cohort 227 subjects with broad A T spectrum. Results The accurate, precise, dilution linear, highly sensitive. All measured samples were within linear range the assay,...
The microtubule-associated protein Tau (MAPT) is a major component of the pathogenesis wide variety brain-damaging disorders, known as tauopathies. These include Alzheimer's disease (AD), denoted secondary tauopathy because obligatory combination with amyloid pathology. In all tauopathies, becomes aberrantly phosphorylated, adopts abnormal conformations, and aggregates into fibrils that eventually accumulate threads in neuropil tangles soma. argyrophilic neurofibrillary tangles, together...
The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular aggregates as a disease-modifying strategy the treatment of Alzheimer's disease (AD) and potentially other tauopathies. As biochemical biophysical properties species responsible spatio-temporal sequences events are poorly defined, it is not yet clear which epitope preferred obtaining optimal therapeutic efficacy. Our internal collection has been...
In Alzheimer's disease (AD) brain, one of the histopathological hallmarks is neurofibrillary tangles consisting aggregated and hyperphosphorylated tau. Currently many tau binding antibodies are under development to target extracellular species responsible for spreading in brain. As such, an in-house developed antibody JNJ-63733657 with picomolar affinity towards phosphorylated at both T212 T217 (further named p217+tau) was recently tested phase I clinical trial NCT03375697. Following...
Background: Early and accurate detection staging is critical to managing Alzheimer’s disease (AD) supporting clinical trials. Cerebrospinal fluid (CSF) biomarkers for amyloid-β peptides, tau species, various neurodegenerative inflammatory analytes are leading the way in this regard, yet there room improved sensitivity specificity. In particular known be present many different fragments, conformations, post-translationally modified forms. While exact species that might best reflect AD...
Multiple animal models have been created to gain insight into Alzheimer's disease (AD) pathology. Among the most commonly used are transgenic mice overexpressing human amyloid precursor protein (APP) with mutations linked familial AD, resulting in formation of β plaques, one pathological hallmarks observed AD patients. However, recent evidence suggests that overexpression APP by itself can confound some reported observations. Therefore, we investigated present study AppNL-G-Fmodel, an App...
As a consequence of the discovery an extracellular component responsible for progression tau pathology, immunotherapy is being extensively explored in both preclinical and clinical studies as disease modifying strategy treatment Alzheimer's disease.Describe characteristics anti-phospho (T212/T217) selective antibody PT3 its humanized variant hPT3.By performing different immunization campaigns, large collection antibodies has been generated prioritized. In depth, vitro characterization using...
The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, forms oligomers and insoluble aggregates that are closely linked to the cause progression of various brain pathologies, including Alzheimer’s disease. Previously we reported development liposome-based vaccines their efficacy safety in preclinical mouse models for tauopathy. Here report use a liposomal vaccine generation monoclonal antibody with particular...
O-β-linked N-acetylglucosaminylation (O-GlcNAcylation) modulates tau phosphorylation and aggregation: the pharmacological increase of O-GlcNAcylation upon treatment with inhibitors O-GlcNAc hydrolase (OGA) constitutes a potential strategy to tackle neurodegenerative diseases. Analysis could potentially be used as pharmacodynamic biomarker both in preclinical clinical studies. The goal current study was confirm at S400 readout OGA inhibition P301S transgenic mice overexpressing human treated...
Clearance of tau seeds by immunization with antibodies is currently evaluated as therapeutic strategy to block the spreading pathology in Alzheimer's disease and other tauopathies. Preclinical evaluation passive immunotherapy performed different cellular culture systems wild-type human transgenic mouse models. Depending on preclinical model used, or induced aggregates can either be mouse, mixed origin.We aimed develop tau-specific discriminate between endogenous introduced form models.Using...
AD patients suffer epileptogenc defects. Time-line analysis of bigenic biAT mice that co-express APP.V717I and Tau.P301L in neurons develop combined Alzheimer pathology (>10-12 months). Important precocious mortality young (<6 months) with epileptic symptoms was totally absent the parental monogenic mice. Neither amyloid nor tauopathy evident brain Amyloid accumulation developed very similar age, while tau phosphorylation oligomerization more early extensive than age-matched Surprisingly,...
Conjugation of b -N-acetylglucosamine to Ser/Thr residues is a reversible post-translational modification many proteins, controlled by two unique enzymes: O-GlcNAc transferase (OGT) and β -N-acetyl-glucosaminidase (OGA). There physiological pathological repercussions significance remain largely unknown in vivo, particularly CNS. Accumulating amyloid peptides aggravate phosphorylation Tau activation GSK3a/b, modeled our bigenic mice biAT biGT (Terwel et al, 2008). Tau.P301L suffer cognitive...
The brain of patients with Alzheimer's disease (AD) is histopathologically characterized by two hallmarks, beta-amyloid plaques and neurofibrillar tangles (NFT) composed hyper-phosphorylated Tau. Tau pathology in the absence overt characteristic a subset frontotemporal dementia (FTD). Progression spreading tau throughout correlates cognitive demise progression AD. Immunotherapy for various neurodegenerative diseases recently emerged as promising approach clearing pathological protein...
The brain of patients with Alzheimer's disease (AD) is characterized by plaques and neurofibrillary tangles (NFT) composed misfolded protein aggregates beta-amyloid hyper-phosphorylated tau, respectively. Immunotherapy can alleviate the pathological impact protein-aggregates as demonstrated in several animal models. correlation between cognitive decline number NFT AD suggests phosphorylated tau (pTau) a promising target for immunotherapy. Tau transgenic mice were immunized over 6-month...
Misfolding of the naturally unfolded protein Tau causes its aggregation into fibrils as yet unknown structure. The aggregates form neurofibrillary tangles in neuronal somata and neuropil threads processes, constituting typical post-mortem pathological signature primary tauopathies. In Alzheimer's disease (AD), tau pathology is presumed secondary to amyloid pathology, but their respective roles relative contributions AD remain open for analysis debate. Therapeutic approaches have prove...