A5073314457- Alzheimer's disease research and treatments
- Neuroinflammation and Neurodegeneration Mechanisms
- Prion Diseases and Protein Misfolding
- Cholinesterase and Neurodegenerative Diseases
- Radiopharmaceutical Chemistry and Applications
- Computational Drug Discovery Methods
- Neurological diseases and metabolism
- Tryptophan and brain disorders
- Neuroscience and Neuropharmacology Research
- Medical Imaging Techniques and Applications
- Monoclonal and Polyclonal Antibodies Research
- Machine Learning in Bioinformatics
- Metabolomics and Mass Spectrometry Studies
- Migraine and Headache Studies
- 14-3-3 protein interactions
- Endoplasmic Reticulum Stress and Disease
- Wnt/β-catenin signaling in development and cancer
- Nuclear Receptors and Signaling
- Stress Responses and Cortisol
- Parkinson's Disease Mechanisms and Treatments
- Cancer-related gene regulation
- Biological Research and Disease Studies
- Neurological Disease Mechanisms and Treatments
- Biotin and Related Studies
- Neuropeptides and Animal Physiology
Lundbeck (Denmark)
2016-2025
New York University
2009-2022
University of Southampton
2008-2015
King's College London
2001-2014
Southampton General Hospital
2010
Psychiatry Research Trust
2003
Merck & Co., Inc., Rahway, NJ, USA (United States)
1998
Immunotherapies for various neurodegenerative diseases have recently emerged as a promising approach clearing pathological protein conformers in these disorders. This type of treatment has not been assessed models that develop neuronal tau aggregates observed frontotemporal dementia and Alzheimer's disease. Here, we present active immunization with phosphorylated epitope, P301L tangle model mice, reduces aggregated the brain slows progression tangle-related behavioral phenotype. Females had...
α-Synuclein is a major protein constituent of Lewy bodies and mutations in α-synuclein cause familial autosomal dominant Parkinson's disease. One explanation for the formation perikaryal neuritic aggregates α-synuclein, which presynaptic protein, that disrupt transport lead to its proximal accumulation. We found mutant forms either associated with disease (A30P or A53T) mimicking defined serine, but not tyrosine, phosphorylation states exhibit reduced axonal following transfection into...
Immunization with amyloid-beta (Abeta) 1-42 has been shown to reduce amyloid burden and improve cognition in Alzheimer's disease (AD) model mice. In a human trial, possible cognitive benefit was found but association significant toxicity minority of patients. We proposed that immunization nonfibrillogenic Abeta derivatives is much less likely produce have previously one such derivative (K6Abeta1-30) can mice similar extent as Abeta1-42. Here, we immunized AD (Tg2576) Abeta1-30[E18E19] or...
Accumulation of β-amyloid (Aβ) in the brain is a key event Alzheimer disease pathogenesis. Apolipoprotein (Apo) E lipid carrier protein secreted by astrocytes, which shows inherent affinity for Aβ and has been implicated receptor-mediated uptake neurons. To characterize ApoE involvement intraneuronal accumulation to investigate whether blocking ApoE/Aβ interaction could reduce buildup, we used noncontact neuronal-astrocytic co-culture system, where synthetic peptides were added into media...
Alzheimer's disease (AD) is a disorder of two pathologies: amyloid plaques, the core which peptide derived from precursor protein (APP), and neurofibrillary tangles composed highly phosphorylated tau. Protein kinase C (PKC) known to increase non-amyloidogenic α-secretase cleavage APP, producing secreted APP (sAPPα), glycogen synthase (GSK)-3β tau phosphorylation. Both PKC GSK-3β are components wnt signaling cascade. Here we demonstrate that overexpression another member this pathway,...
Abstract Immunotherapy holds great promise for Alzheimer's disease (AD) and other conformational disorders but certain adverse reactions need to be overcome. The meningoencephalitis observed in the first AD vaccination trial was likely related excessive cell‐mediated immunity caused by immunogen, amyloid‐β (Aβ) 1–42, adjuvant, QS−21. To avoid this toxicity, we have been using Aβ derivatives alum adjuvant that promotes humoral immunity. Other potential side effects of immunotherapy are...
Accumulation of β-amyloid (Aβ) in the brain is essential to Alzheimer's disease (AD) pathogenesis. Carriers apolipoprotein E (APOE) ε4 allele demonstrate greatly increased AD risk and enhanced Aβ deposition. In contrast, APOE ε2 carries show reduced risk, later age onset, lesser accumulation. However, it remains elusive whether apoE2 isoform exerts truly protective effect against pathology or plays deleterious role albeit less pronounced than apoE4 isoform. Here, we characterized...
Abstract Introduction The abnormal hyperphosphorylation of the microtubule‐associated protein tau plays a crucial role in neurodegeneration Alzheimer's disease (AD) and other tauopathies. Methods Highly specific selective anti‐pS396‐tau antibodies have been generated using peptide immunization with screening against pathologic hyperphosphorylated from rTg4510 mouse AD brains selection vitro vivo seeding assays. Results antibody C10.2 bound specifically to pS396‐tau an IC 50 104 pM detected...
The recent conditional FDA approval of Aducanumab (Adu) for treating Alzheimer's disease (AD) and the continued discussions around that decision have increased interest in immunotherapy AD other brain diseases. Reliable techniques imaging antibodies may guide decision-making future but needs further development. In this study, we used 89Zr-immuno-PET to evaluate targeting distribution a bispecific brain-shuttle IgG based on Adu with transferrin receptor protein-1 (TfR1) shuttling mechanism,...
Abstract Background Pituitary adenylate cyclase-activating peptide (PACAP) is a neuropeptide pivotal in migraine pathophysiology and considered promising new drug target. Although intravenous PACAP triggers attacks recent phase II trial with PACAP-inhibiting antibody showed efficacy prevention, targeting the receptor PAC1 alone has been unsuccessful. The present study investigated role of three receptors (PAC1, VPAC1 VPAC2) inducing migraine-relevant hypersensitivity mice. Methods Hindpaw...
Alzheimer's disease (AD) is characterized by accumulation of amyloid-β (Aβ) species and deposition senile plaques (SPs). Clinical trials with the anti-Aβ antibody aducanumab have been completed recently.To characterize proteomic profile SPs surrounding tissue in a mouse model AD 10-month-old tgAPPPS1-21 mice after chronic treatment for four months weekly dosing (10 mg/kg).After observing significant reduction SP numbers hippocampi aducanumab-treated mice, we applied localized analysis...
We demonstrate that the microtubule-associated protein tau, in form of enhanced green fluorescent (EGFP) is transported along axons neurons culture slow component axonal transport with a speed comparable previously measured<i>in vivo</i>. It was demonstrated EGFP tag has no effect on characteristics, and methodology enables rates individual tau isoforms mutants to be measured. also expressed EGFP-tagged containing either three or four C-terminal repeats zero two N-terminal inserts cultured...
Abstract In the presence of a Wnt signal β‐catenin is spared from proteasomal degradation through complex mechanism involving GSK3β, resulting in transcription target genes. this study we have explored whether GSK3α, related isoform, can also regulate nuclear levels and tau‐directed kinase activity GSK3α are modulated by Wnt. or GSK3β their substrates, tau, were transiently expressed mammalian cells. Immunoblotting revealed that reduces β‐catenin, whilst reporter gene assays demonstrated...
Migraine affects over 1 billion people worldwide and is a leading cause of disability. Targeting the cannabinoid system offers promising approach for pain migraine relief. This study evaluated novel monoacylglycerol lipase (MAGL) inhibitor to prolong endocannabinoid action in acute chronic mouse models migraine. It also examined MAGL receptor (CB1) mRNA expression key head pain-processing regions. C57BL6/J male female mice received human trigger nitroglycerin (NTG) acutely or every other day...
The accelerated approval of the monoclonal antibody (mAb) aducanumab as a treatment option for Alzheimer's Disease and continued discussions about its efficacy have shown that better understanding immunotherapy neurodegenerative diseases is needed. 89Zr-immuno-PET could be suitable tool to open new avenues diagnosis CNS disorders, monitoring disease progression, assessment novel therapeutics.Herein, three different 89 Zr-labeling strategies direct radioiodination with 125 I bispecific...
Migraine is one of the most disabling diseases that continues to pose a significant societal burden. Although there are now treatment options for people with migraine, it remains challenging identify them as clinical features diverse and complex, no validated diagnostic or prediction biomarkers. Identification based on either coding use certain acute headache abortive treatments. However, socioeconomic disparities can contribute under-diagnosis under-treatment migraine. Thus, efforts find...
Members of the cyclic-AMP response-element binding protein (CREB) transcription factor family regulate expression genes needed for long-term memory formation. Loss Notch impairs long-term, but not short-term, in flies and mammals. We investigated if Notch-1 (N1) exerts an effect on CREB-dependent gene transcription. observed that N1 inhibits CREB mediated activation response element (CRE) containing promoters a γ-secretase-dependent manner. went to find γ-cleaved intracellular domain (N1ICD)...
Proteolytic cleavage of the amyloid precursor protein (APP) generates β-amyloid (Aβ) peptides. Prolonged accumulation Aβ in brain underlies pathogenesis Alzheimer disease (AD) and is regarded as a principal target for development disease-modifying therapeutics.Using Chinese hamster ovary (CHO) APP751SW cells, we identified characterized effects 2-([pyridine-2-ylmethyl]-amino)-phenol (2-PMAP) on APP steady-state level production. Outcomes 2-PMAP treatment associated memory deficit were...
Photoincorporation of ligands into the benzodiazepine site native γ-aminobutyric acid<sub>A</sub> (GABA<sub>A</sub>) receptors provides useful information about nature (BZ) binding site. flunitrazepam a single population GABA<sub>A</sub> receptors, recombinant human α1β3γ2, was investigated to probe further mechanism and orientation other in BZ It concluded that receptor is primarily derivatized with entire, unfragmented, molecule, which undergoes conformational change during photolysis...