Papers by Oskar Th Adolfsson
Journal of Alzheimer's disease : JAD, 2017
The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protei... more The microtubule-associated protein Tau is an intrinsically unfolded, very soluble neuronal protein. Under still unknown circumstances, Tau protein forms soluble oligomers and insoluble aggregates that are closely linked to the cause and progression of various brain pathologies, including Alzheimer's disease. Previously we reported the development of liposome-based vaccines and their efficacy and safety in preclinical mouse models for tauopathy. Here we report the use of a liposomal vaccine for the generation of a monoclonal antibody with particular characteristics that makes it a valuable tool for fundamental studies as well as a candidate antibody for diagnostic and therapeutic applications. The specificity and affinity of antibody ACI-5400 were characterized by a panel of methods: (i) measuring the selectivity for a specific phospho-Tau epitope known to be associated with tauopathy, (ii) performing a combination of peptide and protein binding assays, (iii) staining of brain se...
Scientific reports, Dec 20, 2016
Accumulation of amyloid-β (Aβ) peptides and amyloid plaque deposition in brain is postulated as a... more Accumulation of amyloid-β (Aβ) peptides and amyloid plaque deposition in brain is postulated as a cause of Alzheimer's disease (AD). The precise pathological species of Aβ remains elusive although evidence suggests soluble oligomers may be primarily responsible for neurotoxicity. Crenezumab is a humanized anti-Aβ monoclonal IgG4 that binds multiple forms of Aβ, with higher affinity for aggregated forms, and that blocks Aβ aggregation, and promotes disaggregation. To understand the structural basis for this binding profile and activity, we determined the crystal structure of crenezumab in complex with Aβ. The structure reveals a sequential epitope and conformational requirements for epitope recognition, which include a subtle but critical element that is likely the basis for crenezumab's versatile binding profile. We find interactions consistent with high affinity for multiple forms of Aβ, particularly oligomers. Of note, crenezumab also sequesters the hydrophobic core of Aβ ...
World Journal of Gastroenterology, 2006
AIM: Different strains of bifidobacteria were analysed for their effects on HT-29 intestinal epit... more AIM: Different strains of bifidobacteria were analysed for their effects on HT-29 intestinal epithelial cells (IECs) in in vitro models both of the non-inflamed and inflamed intestinal epithelium. CONCLUSION: Some strains of bifidobacteria are effective in inhibiting LPS-induced inflammation and thus might be appropriate candidates for probiotic intervention in chronic intestinal inflammation.
<p>(A) Vaccination schedule with ACI-35 in wild-type mice is shown schematically with s.c. ... more <p>(A) Vaccination schedule with ACI-35 in wild-type mice is shown schematically with s.c. injections represented by the syringes and the bleedings by the letter B with a number. Antisera titers were measured by ELISA on the phosphorylated antigenic sequence incorporated in the vaccine (pTau peptide), and on the non-phosphorylated peptide of the same primary amino acid sequence (Tau peptide) (see text for details). Data are presented as mean± SD. Statistical analysis: one-way ANOVA followed by Bonferroni multiple comparison test (**p<0.01, **** p<0.0001) and by unpaired student's t-test (**** p<0.0001). (B) Similar vaccination with ACI-35 of Tau.P301L mice and analysis by ELISA. Data are presented as mean± SD. Statistical analysis by unpaired student's t-test (** p<0.01; **** p<0.0001) (C) TAUPIR with antisera from ACI-35 vaccinated wild-type mice and Tau.P301L mice demonstrated a specific reaction with neurofibrillary tangles and neuropil threads in forebrain of biGT mice. IHC with Mab AT100 is included for comparison. IHC with sera from Tau.P301L mice injected with PBS or from Tau.P301L mice that were not vaccinated, were devoid of specific antibodies and auto-antibodies against human protein Tau. Scale bars: 50 µm.</p
World Journal of Gastroenterology
Nestl� Nutrition Workshop Series: Clinical & Performance Program, 2002
The American journal of clinical nutrition, 2004
In recent years, numerous studies have been published on the health effects of yogurt and the bac... more In recent years, numerous studies have been published on the health effects of yogurt and the bacterial cultures used in the production of yogurt. In the United States, these lactic acid-producing bacteria (LAB) include Lactobacillus and Streptococcus species. The benefits of yogurt and LAB on gastrointestinal health have been investigated in animal models and, occasionally, in human subjects. Some studies using yogurt, individual LAB species, or both showed promising health benefits for certain gastrointestinal conditions, including lactose intolerance, constipation, diarrheal diseases, colon cancer, inflammatory bowel disease, Helicobacter pylori infection, and allergies. Patients with any of these conditions could possibly benefit from the consumption of yogurt. The benefits of yogurt consumption to gastrointestinal function are most likely due to effects mediated through the gut microflora, bowel transit, and enhancement of gastrointestinal innate and adaptive immune responses. ...
Journal of Alzheimers Disease, 2014
World Journal of Gastroenterology, 2011
AIM: To assess the anti-inflammatory effect of the probiotic Bifidobacterium lactis (B. lactis) i... more AIM: To assess the anti-inflammatory effect of the probiotic Bifidobacterium lactis (B. lactis) in an adoptive transfer model of colitis. METHODS: Donor and recipient mice received either B. lactis or bacterial culture medium as control (deMan Rogosa Sharpe) in drinking water for one week prior to transfer of a mix of naive and regulatory T cells until sacrifice. RESULTS: All recipient mice developed signs of colonic inflammation, but a significant reduction of weight loss was observed in B. lactis-fed recipient mice compared to control mice. Moreover, a trend toward a diminution of mucosal thickness and attenuated epithelial damage was revealed. Colonic expression of pro-inflammatory and T cell markers was significantly reduced in B. lactisfed recipient mice compared to controls. Concomitantly, forkhead box protein 3, a marker of regulatory T cells, was significantly up-regulated by B. lactis. CONCLUSION: Daily oral administration of B. lactis was able to reduce inflammatory and T cells mediators and to promote regulatory T cells specific markers in a mouse model of colitis.
Journal of Neuroscience, 2012
Passive immunization against -amyloid (A) has become an increasingly desirable strategy as a th... more Passive immunization against -amyloid (A) has become an increasingly desirable strategy as a therapeutic treatment for Alzheimer's disease (AD). However, traditional passive immunization approaches carry the risk of Fc␥ receptor-mediated overactivation of microglial cells, which may contribute to an inappropriate proinflammatory response leading to vasogenic edema and cerebral microhemorrhage. Here, we describe the generation of a humanized anti-A monoclonal antibody of an IgG4 isotype, known as MABT5102A (MABT). An IgG4 subclass was selected to reduce the risk of Fc␥ receptor-mediated overactivation of microglia. MABT bound with high affinity to multiple forms of A, protected against A1-42 oligomer-induced cytotoxicity, and increased uptake of neurotoxic A oligomers by microglia. Furthermore, MABT-mediated amyloid plaque removal was demonstrated using in vivo live imaging in hAPP (V717I) /PS1 transgenic mice. When compared with a human IgG1 wild-type subclass, containing the same antigen-binding variable domains and with equal binding to A, MABT showed reduced activation of stress-activated p38MAPK (p38 mitogen-activated protein kinase) in microglia and induced less release of the proinflammatory cytokine TNF␣. We propose that a humanized IgG4 anti-A antibody that takes advantage of a unique A binding profile, while also possessing reduced effector function, may provide a safer therapeutic alternative for passive immunotherapy for AD. Data from a phase I clinical trial testing MABT is consistent with this hypothesis, showing no signs of vasogenic edema, even in ApoE4 carriers.
Rheumatology, 2009
Objectives. To investigate the expression and function of triggering receptor expressed on myeloi... more Objectives. To investigate the expression and function of triggering receptor expressed on myeloid cells-1 (TREM-1) in the synovium of human RA patients as well as the level of soluble TREM-1 in the plasma of RA patients. Methods. Twenty-four RA synovial samples were analysed by gene expression oligonucleotide microarrays. Expression levels of TREM-1 mRNA in murine CIA paws were determined by quantitative PCR (qPCR). TREM-1 protein expression was detected by immunohistochemistry in five RA synovial samples and two OA synovial samples. TREM-1-positive cells from five RA synovial tissues were analysed by FACS staining to determine the cell type. Activation of TREM-1 was tested in five RA synovial samples. Soluble TREM-1 was measured in serum from 32 RA patients. Results. The expression of TREM-1 mRNA was found to increase 6.5-fold in RA synovial samples, whereas it was increased 132-fold in CIA paws. Increased numbers of TREM-1-positive cells were seen in RA synovium sections and these cells co-expressed CD14. Using a TREM-1-activating cross-linking antibody in RA synovial cultures, multiple pro-inflammatory cytokines were induced. The average amount of soluble TREM-1 in plasma from RA patients was found to be higher than that in plasma from healthy volunteers. Conclusions. These findings suggest that the presence of high levels of functionally active TREM-1 in RA synovium may contribute to the development or maintenance of RA, or both. Inhibiting TREM-1 activity may, therefore, have a therapeutic effect on RA. High levels of soluble TREM-1 in the plasma of RA patients compared with healthy volunteers may indicate disease activity.
PLoS ONE, 2013
Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decli... more Progressive aggregation of protein Tau into oligomers and fibrils correlates with cognitive decline and synaptic dysfunction, leading to neurodegeneration in vulnerable brain regions in Alzheimer's disease. The unmet need of effective therapy for Alzheimer's disease, combined with problematic pharmacological approaches, led the field to explore immunotherapy, first against amyloid peptides and recently against protein Tau. Here we adapted the liposome-based amyloid vaccine that proved safe and efficacious, and incorporated a synthetic phosphorylated peptide to mimic the important phospho-epitope of protein Tau at residues pS396/pS404. We demonstrate that the liposome-based vaccine elicited, rapidly and robustly, specific antisera in wild-type mice and in Tau.P301L mice. Long-term vaccination proved to be safe, because it improved the clinical condition and reduced indices of tauopathy in the brain of the Tau.P301L mice, while no signs of neuroinflammation or other adverse neurological effects were observed. The data corroborate the hypothesis that liposomes carrying phosphorylated peptides of protein Tau have considerable potential as safe and effective treatment against tauopathies, including Alzheimer's disease.
Nutrition Research, 2000
A.A. BEHARKA et al. E and melatonin may be partially responsible for the reduction in unstimulate... more A.A. BEHARKA et al. E and melatonin may be partially responsible for the reduction in unstimulated IL-6 production. LPS stimulation resulted in production of IL-lj3, IL-6, IL-lo, IL-12, IL-15, NO, PGE,, and TNF-a by peritoneal or bone marrow (BM)-derived M+. Of these, only NO production was modulated by antioxidant supplementation and then significantly by vitamin E only. Vitamin E supplementation reduced the age-related increase in inducible NO production by peritoneal M$ (p<O.OS), but not by BM M$. In conclusion, vitamin E modulated production of at least three, and melatonin modulated production of at least two, molecules produced by M$I, which are involved in a variety of age-associated chronic and acute inflammatory diseases. Further research is needed to determine the mechanisms and clinical benefits of E and melatonin-induced reduction in M$ inflammatory mediator production. 0 ?"o(I hlacvler s<,nlcr Inc
Molecular Nutrition & Food Research, 2008
Advanced glycation endproducts (AGEs) containing carboxymethyllysine (CML) modifications are gene... more Advanced glycation endproducts (AGEs) containing carboxymethyllysine (CML) modifications are generally thought to be ligands of the receptor for AGEs, RAGEs. It has been argued that this results in the activation of pro‐inflammatory pathways and diseases. However, it has not been shown conclusively that a CML‐modified protein can interact directly with RAGE. Here, we have analyzed whether beta‐lactoglobulin (bLG) or human serum albumin (HSA) modified chemically to contain only CML (10–40% lysine modification) can (i) interact with RAGE in vitro and (ii) interact with and activate RAGE in lung epithelial cells. Our results show that CML‐modified bLG or HSA are unable to bind to RAGE in a cell‐free assay system (Biacore). Furthermore, they are unable to activate pro‐inflammatory signaling in the cellular system. Thus, CML probably does not form the necessary structure(s) to interact with RAGE and activate an inflammatory signaling cascade in RAGE‐expressing cells.
The Journal of Immunology, 2001
Aging is associated with reduced T cell function, as demonstrated by decreased T cell proliferati... more Aging is associated with reduced T cell function, as demonstrated by decreased T cell proliferation and IL-2 production. These changes respond to supplemental vitamin E both in animals and humans, in part by the reduction of T cell suppressive PGE2, the production of which by macrophages is increased with age. To evaluate whether vitamin E has a direct PGE2-independent effect on T cell responses, T cells purified from the spleens of young and old mice were preincubated with vitamin E or vehicle control. Activation-induced cell division of T cells from old mice was lower than that by young, and the production of IL-2 following 48-h activation was less by T cells from old mice. There was an age-related decline in both the number of IL-2+ T cells and the amount of IL-2 produced per cell. Despite decreased IL-2 protein at 48 h, the expression of IL-2 mRNA at 6 h and IL-2 protein production at 6 and 16 h was greater by T cells from old mice compared with that of young. Age-related declin...
The Journal of Immunology, 2006
T cells are vulnerable to age-associated changes. Vitamin E has been shown to improve T cell func... more T cells are vulnerable to age-associated changes. Vitamin E has been shown to improve T cell functions in the old. We studied gene expression profiles of T cells to better understand the underlying mechanisms of age and vitamin E-induced changes in T cell function. Young and old C57BL mice were fed diets containing 30 (control) or 500 (supplemented) ppm of vitamin E for 4 wks. Gene expression profiles of T cells were assessed using microarray analysis with/without anti-CD3/anti-CD28 stimulation. Genes associated with cytokines/chemokines, transcriptional regulation, signal transduction, cell cycle, and apoptosis were significantly up-regulated upon stimulation. Higher SOCS3 and lower growth factor independent 1 (Gfi-1) expression in old T cells may contribute to age-associated decline in proliferation. Higher Gadd45 and lower Bcl2 expression may contribute to increased apoptosis in old T cells. Vitamin E supplementation resulted in higher expression of genes involved in cell cycle r...
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Papers by Oskar Th Adolfsson