A5055348919- Alzheimer's disease research and treatments
- Monoclonal and Polyclonal Antibodies Research
- Prion Diseases and Protein Misfolding
- Computational Drug Discovery Methods
- Neuroinflammation and Neurodegeneration Mechanisms
- Radiopharmaceutical Chemistry and Applications
- Click Chemistry and Applications
- Neuroscience and Neuropharmacology Research
- Amyloidosis: Diagnosis, Treatment, Outcomes
- Glycosylation and Glycoproteins Research
- S100 Proteins and Annexins
- Parkinson's Disease Mechanisms and Treatments
- Protein Structure and Dynamics
- 14-3-3 protein interactions
- Advanced Biosensing Techniques and Applications
- RNA Interference and Gene Delivery
- Supramolecular Self-Assembly in Materials
- Chemical Synthesis and Analysis
- Drug Transport and Resistance Mechanisms
- Advanced biosensing and bioanalysis techniques
- Extracellular vesicles in disease
- Cholinesterase and Neurodegenerative Diseases
- Neurological disorders and treatments
- Aluminum toxicity and tolerance in plants and animals
- Cerebrospinal fluid and hydrocephalus
Uppsala University
2016-2025
Mabtech (Sweden)
2010
Florida College
1973
University of Florida
1973
Carnegie Mellon University
1973
University of Wisconsin–Madison
1973
Despite the clear physical association between activated astrocytes and amyloid-β (Aβ) plaques, importance of their therapeutic potential in Alzheimer's disease remain elusive. Soluble Aβ aggregates, such as protofibrils, have been suggested to be responsible for widespread neuronal cell death disease, but mechanisms behind this unclear. Moreover, ineffective degradation is great interest when it comes development progression neurodegeneration. Based on our previous results that are...
Abstract Owing to their specificity and high-affinity binding, monoclonal antibodies have potential as positron emission tomography (PET) radioligands are currently used image various targets in peripheral organs. However, the central nervous system, antibody uptake is limited by blood–brain barrier (BBB). Here we present a PET ligand be for diagnosis evaluation of treatment effects Alzheimer’s disease. The amyloid β (Aβ) mAb158 radiolabelled conjugated transferrin receptor enable...
The blood-brain barrier (BBB) is an obstacle for antibody passage into the brain, impeding development of immunotherapy and antibody-based diagnostics brain disorders. In present study, we have developed a shuttle active transport antibodies across BBB by receptor-mediated transcytosis. We thus recombinantly fused two single-chain variable fragments (scFv) transferrin receptor (TfR) 8D3 to light chains mAb158, selectively binding Aβ protofibrils, which are involved in pathogenesis...
Abstract Amyloid‐β (Aβ) protofibrils are known intermediates of the in vitro Aβ aggregation process and protofibrillogenic Arctic mutation (APPE693G) provides clinical support for a pathogenic role Alzheimer’s disease (AD). To verify their vivo relevance to establish quantitative protofibril immunoassay, conformation dependent monoclonal antibodies were generated. One these antibodies, mAb158 (IgG2a), was used sandwich ELISA specifically detect picomolar concentrations without interference...
Soluble amyloid-β (Aβ) aggregates of various sizes, ranging from dimers to large protofibrils, have been associated with neurotoxicity and synaptic dysfunction in Alzheimer's Disease (AD). To investigate the properties biologically relevant Aβ species, brain extracts amyloid β protein precursor (AβPP) transgenic mice AD patients as well synthetic preparations were separated by size under native conditions density gradient ultracentrifugation. The fractionated samples then analyzed atomic...
Immunotherapy is a very fast expanding field within drug discovery and, hence, rapid and inexpensive expression of antibodies would be extremely valuable. Antibodies are, however, difficult to express. Multifunctional with additional binding domains further complicate the expression. Only few protocols describe production tetravalent bispecific all limited levels. Here, we protocol that can produce functional tetravalent, at around 22 mg protein/l low cost. The system based on Expi293 cells,...
The major pathological hallmarks of Alzheimer's disease (AD) are the progressive aggregation and accumulation beta-amyloid (Aβ) hyperphosphorylated tau protein into neurotoxic deposits. Aβ has been suggested as critical early inducer, driving progression. However, factors that promote remain elusive. Imaging mass spectrometry (IMS) is a powerful technique to comprehensively elucidate spatial distribution patterns lipids, peptides, proteins in biological tissue sections. In present study,...
Evidence suggests that amyloid-β (Aβ) protofibrils/oligomers are pathogenic agents in Alzheimer's disease (AD). Unfortunately, techniques enabling quantitative estimates of these species patients or patient samples still rather limited. Here w
In Parkinson's disease and other Lewy body disorders, the propagation of pathology has been accredited to spreading extracellular α-synuclein (α-syn). Although pathogenic mechanisms are not fully understood, cell-to-cell transfer α-syn via exosomes vesicles (EVs) reported. Here, we investigated whether altered molecular properties can influence distribution secretion in human neuroblastoma cells. Different variants, including α-syn:hemi-Venus disease-causing mutants, were overexpressed EVs...
PET imaging of amyloid-beta (Aβ) deposits in brain has become an important aid Alzheimer's disease diagnosis, and inclusion criterion for patient enrolment into clinical trials new anti-Aβ treatments. Available radioligands visualizing Aβ bind to insoluble fibrils, i.e. plaques. Levels prefibrillar forms, e.g. soluble oligomers protofibrils, correlate better than plaques with severity these species are the neurotoxic form leading neurodegeneration. The goal was create antibody-based...
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-beta (Aβ) deposition, hyperphosphorylation of tau, and neuroinflammation. Astrocytes, the most abundant glial cell type in nervous system, respond to disorders through astrogliosis, i.e., converting reactive inflammatory state. The aim this study was investigate how vivo quantification astrogliosis using positron emission tomography (PET) radioligand deuterium-l-[11C]deprenyl ([11C]DED), binding enzyme...
Amyloid-β (Aβ) immunotherapy is one of the most promising disease-modifying strategies for Alzheimer's disease (AD). Despite recent progress targeting aggregated forms Aβ, low antibody brain penetrance remains a challenge. In present study, we used transferrin receptor (TfR)-mediated transcytosis to facilitate uptake our previously developed Aβ protofibril-selective mAb158, with aim increasing efficacy directed toward soluble protofibrils. protein precursor (AβPP)-transgenic mice (tg-ArcSwe)...
Transferrin receptor (TfR1) mediated enhanced brain delivery of antibodies have been studied extensively in preclinical settings. However, the pharmacokinetics, i.e. entry, distribution and elimination are still not fully understood for this class antibodies. The overall aim study was to compare pharmacokinetics two BBB-penetrating bispecific different size (210 vs 58 kDa). Specifically, we wanted investigate if faster systemic clearance smaller non-IgG antibody di-scFv3D6-8D3, comparison...
Abstract Background Alzheimer’s disease (AD) immunotherapy with antibodies targeting amyloid-β (Aβ) has been extensively explored in clinical trials. The aim of this study was to the long-term brain distribution two radiolabeled monoclonal Aβ antibody variants – RmAb158, recombinant murine version BAN2401, which recently demonstrated amyloid removal and reduced cognitive decline AD patients, bispecific RmAb158-scFv8D3, engineered for enhanced uptake via transferrin receptor-mediated...
The protein alpha-synuclein (αSYN) plays a central role in synucleinopathies such as Parkinsons's disease (PD) and multiple system atrophy (MSA). Presently, there are no selective αSYN positron emission tomography (PET) radioligands that do not also show affinity to amyloid-beta (Aβ). We have previously shown radiolabeled antibodies, engineered enter the brain via transferrin receptor (TfR), is promising approach for PET imaging of intrabrain targets. In this study, we used strategy...
The use of transgenic mice displaying amyloid-β (Aβ) brain pathology has been essential for the preclinical assessment new treatment strategies Alzheimer's disease. However, properties Aβ in such have not systematically compared to brains patients with Here, we determined structures nine ex vivo fibrils from six different mouse models by cryogenic-electron microscopy. We found novel fibril APP/PS1, ARTE10 and tg-SwDI models, whereas human type II filament fold was ARTE10, tg-APPSwe APP23...
Currently, several amyloid beta (Aβ) antibodies, including the protofibril selective antibody BAN2401, are in clinical trials. The murine version of mAb158, has previously been shown to lower levels pathogenic Aβ and prevent deposition animal models Alzheimer's disease (AD). However, cellular mechanisms antibody's action remain unknown. We have recently that astrocytes effectively engulf Aβ42 protofibrils, but store rather than degrade ingested aggregates. In a co-culture set-up, incomplete...
Transferrin receptor 1 (TfR1) mediated transcytosis is an attractive strategy to enhance brain uptake of protein drugs, but translation remains a challenge. Here, single domain shark antibody VNAR fragment (TXB2) with similar affinity murine and human TfR1 was used shuttle cargo into the brain. TXB2 fused IgG1 Fc (hFc) or amyloid-β (Aβ) bapineuzumab (Bapi). TXB2-hFc displayed 20-fold higher concentrations compared control VNAR-hFc at 18 hours post-injection in wt mice. At same time point,...
Abstract Alzheimer’s disease (AD) is characterized by a substantial loss of neurons and synapses throughout the brain. The exact mechanism behind neurodegeneration still unclear, but recent data suggests that spreading amyloid-β (Aβ) pathology via extracellular vesicles (EVs) may contribute to progression. We have previously shown an incomplete degradation Aβ 42 protofibrils astrocytes results in release EVs containing neurotoxic Aβ. Here, we describe cellular mechanisms EV-associated...
The Uppsala APP deletion leads to Alzheimer’s disease by modulating α- and β-secretase cleavage of accelerating Aβ fibrillization.
Amyloid-β (Aβ) immunotherapy is a promising therapeutic strategy in the fight against Alzheimer's disease (AD). A number of monoclonal antibodies have entered clinical trials for AD. Some them failed due to lack efficacy or side-effects, two are currently phase 3, and one has been approved by FDA. The soluble intermediate aggregated species Aβ, termed oligomers protofibrils, believed be key pathogenic forms, responsible synaptic neuronal degeneration Therefore, that can strongly selectively...