| 1. |
- Borgegard, Tomas, et al.
(författare)
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Alzheimers Disease: Presenilin 2-Sparing gamma-Secretase Inhibition Is a Tolerable A beta Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - : Society for Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- gamma-Secretase inhibition represents a major therapeutic strategy for lowering amyloid beta (A beta) peptide production in Alzheimers disease (AD). Progress toward clinical use of gamma-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The gamma-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between A beta production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1(PS1) over PS2 subclass of gamma-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain A beta levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious gamma-secretase targeting strategy for AD.
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| 2. |
- Borgegård, Tomas, et al.
(författare)
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Alzheimer's Disease : Presenilin 2-Sparing γ-Secretase Inhibition Is a Tolerable Aβ Peptide-Lowering Strategy
- 2012
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Ingår i: Journal of Neuroscience. - 0270-6474 .- 1529-2401. ; 32:48, s. 17297-17305
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Tidskriftsartikel (refereegranskat)abstract
- γ-Secretase inhibition represents a major therapeutic strategy for lowering amyloid β (Aβ) peptide production in Alzheimer's disease (AD). Progress toward clinical use of γ-secretase inhibitors has, however, been hampered due to mechanism-based adverse events, primarily related to impairment of Notch signaling. The γ-secretase inhibitor MRK-560 represents an exception as it is largely tolerable in vivo despite displaying only a small selectivity between Aβ production and Notch signaling in vitro. In exploring the molecular basis for the observed tolerability, we show that MRK-560 displays a strong preference for the presenilin 1 (PS1) over PS2 subclass of γ-secretases and is tolerable in wild-type mice but causes dose-dependent Notch-related side effect in PS2-deficient mice at drug exposure levels resulting in a substantial decrease in brain Aβ levels. This demonstrates that PS2 plays an important role in mediating essential Notch signaling in several peripheral organs during pharmacological inhibition of PS1 and provide preclinical in vivo proof of concept for PS2-sparing inhibition as a novel, tolerable and efficacious γ-secretase targeting strategy for AD.
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| 3. |
- Charney, Alexander W, et al.
(författare)
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Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases.
- 2019
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Ingår i: Biological psychiatry. - : Elsevier BV. - 1873-2402 .- 0006-3223. ; 86:2, s. 110-119
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Tidskriftsartikel (refereegranskat)abstract
- Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. Subtypes of BD including schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I), and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania, and depression. The genetic factors contributing to the combination of symptoms among these subtypes are poorly understood.Rare large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis, and 307 with unknown psychosis history], 1436 BD II, 579 SAB, and 505 BD not otherwise specified) and 8656 controls. CNV burden and a polygenic risk score (PRS) for schizophrenia were used to evaluate the relative contributions of rare and common variants to risk of BD, BD subtypes, and psychosis.CNV burden did not differ between BD and controls when treated as a single diagnostic entity. However, burden in SAB was increased relative to controls (p = .001), BD I (p = .0003), and BD II (p = .0007). Burden and schizophrenia PRSs were increased in SAB compared with BD I with psychosis (CNV p = .0007, PRS p = .004), and BD I without psychosis (CNV p = .0004, PRS p = 3.9 × 10-5). Within BD I, psychosis was associated with increased schizophrenia PRSs (p = .005) but not CNV burden.CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.
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| 4. |
- Forsberg, Anton, et al.
(författare)
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Low background and high contrast PET imaging of amyloid-β with [11C]AZD2995 and [11C]AZD2184 in Alzheimer's disease patients
- 2013
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Ingår i: European Journal of Nuclear Medicine and Molecular Imaging. - : Springer-Verlag New York. - 1619-7070 .- 1619-7089. ; 40:4, s. 580-593
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: The aim of this study was to evaluate AZD2995 side by side with AZD2184 as novel PET radioligands for imaging of amyloid-β in Alzheimer's disease (AD).METHODS: In vitro binding of tritium-labelled AZD2995 and AZD2184 was studied and compared with that of the established amyloid-β PET radioligand PIB. Subsequently, a first-in-human in vivo PET study was performed using [(11)C]AZD2995 and [(11)C]AZD2184 in three healthy control subjects and seven AD patients.RESULTS: AZD2995, AZD2184 and PIB were found to share the same binding site to amyloid-β. [(3)H]AZD2995 had the highest signal-to-background ratio in brain tissue from patients with AD as well as in transgenic mice. However, [(11)C]AZD2184 had superior imaging properties in PET, as shown by larger effect sizes comparing binding potential values in cortical regions of AD patients and healthy controls. Nevertheless, probably due to a lower amount of nonspecific binding, the group separation of the distribution volume ratio values of [(11)C]AZD2995 was greater in areas with lower amyloid-β load, e.g. the hippocampus.CONCLUSION: Both AZD2995 and AZD2184 detect amyloid-β with high affinity and specificity and also display a lower degree of nonspecific binding than that reported for PIB. Overall [(11)C]AZD2184 seems to be an amyloid-β radioligand with higher uptake and better group separation when compared to [(11)C]AZD2995. However, the very low nonspecific binding of [(11)C]AZD2995 makes this radioligand potentially interesting as a tool to study minute levels of amyloid-β. This sensitivity may be important in investigating, for example, early prodromal stages of AD or in the longitudinal study of a disease modifying therapy.
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| 5. |
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| 6. |
- Juréus, Anders, 1970-
(författare)
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Galanin : Studies by Modification of the Ligand and the Receptor
- 1998
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is devoted to the deeper understanding of the molecular details of the interaction between the neuropeptide galanin and its target protein, the G-protein coupled 7TM galanin receptor. The enzymatic control of galanin degradation and second messenger systems triggered by galanin receptor activation are also studied.Galanin analogs with substitutions of amino acids by units of L-Ala residues have been developed as selective ligands to galanin receptor subtypes in the rat hypothalamus and in the rat jejunum. It is shown that galanin receptors in the jejunum require also the C-terminal segment KHGLT25-29for receptor recognition in contrast to receptors in the hypothalamus which only interact with the N-terminal portion (1-13) of galanin.It is confirmed that the N-terminal portion (1-13) of galanin is essential for receptor recognition in the rat hypothalamus and that the C-terminus of the ligand can be extended with sequences of amino acids or other organic structures to increase the affinity of the N-terminal (1-13) fragment of galanin. It is also concluded that a minimum motif required for galanin receptor recognition should contain the indol structure of a Trp residue and the aromatic side chain of a Tyr residue plus one additional bulky highly hydrophobic structure as well as some positively charged structures.The galanin binding domains of the receptor, GalR1 have been studied by site directed mutagenesis and a structural model for the interaction of the major pharmacophores of galanin is proposed. The charged N-terminus of galanin is suggested to interact with Phe115 in TM III by cation-p interaction, the Trp2 residue of galanin is proposed to interact with a pair of His residues located at the top of TM VI and the Tyr9 of galanin is interacting with another phenylalanine, Phe282 in the EC III of the receptor. One of the two histidine residues (264,267); His267is believed not only to be important for ligand binding but also is stabilising the active conformation of the GalR1 receptor, important for the G-protein coupling of the agonist occupied receptor.It is shown that galanin binding sites are present at significantly higher numbers in the ventral part of the rat hippocampus compared to the dorsal area. Furthermore it is determined that the efficiency of the inhibitory coupling to basal and forskolin stimulated cAMP production by galanin receptors is 250 fold less potent in the dorsal region of the rat hippocampus. The differences in regulation of adenylate cyclase suggests an unequal receptor subtype distribution in the dorsal and ventral hippocampus with higher levels of Gicoupled GalR1 receptors in the ventral segments of the hippocampal formation.An internally quenched fluorescent substrate for galanin degrading enzymes has been developed and used for purification of a galanin inactivating 70 kDa membrane associated metallo-endopeptidase from bovine spinal cord. The enzyme that has a inhibitor profile different from NEP-24.11 primarily cleaves galanin between Trp2 and Thr3 and recognises both galanin and the galanin mimicking fluorescent artificial substrate with high affinity. This cleavage generates products that are inactive at both GalR1 and GalR2 receptors.
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| 7. |
- Juréus, Jan, et al.
(författare)
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The natural course of spontaneous osteonecrosis of the knee (SPONK) A 1-to 27-year follow-up of 40 patients
- 2013
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Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 84:4, s. 410-414
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Spontaneous osteonecrosis of the knee (SPONK) is a painful lesion in the elderly, frequently leading to osteoarthritis and subsequent knee surgery. We evaluated the natural course and long-term consequences of SPONK in terms of need for major knee surgery. Methods Between 1982 and 1988, 40 consecutive patients were diagnosed with SPONK. The short-term outcome has been reported previously (1991). After 1-7 years, 10 patients had a good radiographic outcome and 30 were considered failures, developing osteoarthritis. In 2012, all 40 of the patients were matched with the Swedish Knee Arthroplasty Register (SKAR) and their medical records were reviewed to evaluate the long-term need for major knee surgery. Results At the 2012 review, 33 of the 40 patients had died. The mean follow-up time from diagnosis to surgery, death, or end of study was 9 (1-27) years. 17 of 40 patients had had major knee surgery with either arthroplasty (15) or osteotomy (2). All operated patients but 1 were in the radiographic failure group and had developed osteoarthritis in the study from 1991. 6 of 7 patients with large lesions (> 40% of the AP radiographic view of the condyle) at the time of the diagnosis were operated. None of the 10 patients with a lesion of less than 20% were ever operated. Interpretation It appears that the size of the osteonecrotic lesion can be used to predict the outcome. Patients showing early signs of osteoarthritis or with a large osteonecrosis have a high risk of later major knee surgery.
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| 8. |
- Juréus, Jan, et al.
(författare)
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Treatment of spontaneous osteonecrosis of the knee (SPONK) by a bisphosphonate A prospective case series with 17 patients
- 2012
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Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3682 .- 1745-3674. ; 83:5, s. 511-514
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Primary spontaneous osteonecrosis of the knee is a painful lesion in the elderly without any known cause. The onset of pain is usually acute. The prognosis is poor with high frequency of osteoarthritis, joint surface collapse, and subsequent knee surgery. In the present study, we determined whether bisphosphonates can prevent the joint surface collapse by delaying the post-necrotic remodeling. Patients and methods Between 2006 and 2009, 17 consecutive patients (mean age 68 years) with clinical and radiographic signs of knee osteonecrosis were identified and given alendronate, 70 mg perorally, once a week for a minimum of 6 months. The patients were followed clinically, radiographically, and by MRI. Results 10 of the 17 patients did not develop osteoarthritis (group A), 4 patients developed mild osteoarthritis but no knee joint surface collapse (group B), and 3 patients had a joint surface collapse (group C). 2 of the 3 patients in group C-as compared to none in the other groups-stopped medication prematurely, due to side effects. Interpretation Compared to a previous, untreated series of osteonecrosis patients at our hospital, the clinical results in the present series appeared better. 59% of the patients had a complete radiographic recovery, as compared to 25% in the original study. 12% were failures regarding need to undergo surgery when bisphosphonates were given, as compared to 32% in the previous untreated series. An anticatabolic drug delaying the remodeling might be an effective treatment in osteonecrosis of the knee but further (preferably randomized) studies are necessary.
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