Browsing by Subject "Amyloid-beta"

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  • Ni, Ruiqing; Gillberg, Per-Goran; Bogdanovic, Nenad; Viitanen, Matti; Myllykangas, Liisa; Nennesmo, Inger; Langstrom, Bengt; Nordberg, Agneta (2017)
    Introduction: Amyloid imaging has been integrated into diagnostic criteria for Alzheimer's disease (AD). How amyloid tracers binding differ for different tracer structures and amyloid-beta aggregates in autosomal dominant AD (ADAD) and sporadic AD is unclear. Methods: Binding properties of different amyloid tracers were examined in brain homogenates from six ADAD with APPswe, PS1 M146V, and PS1 E Delta 9 mutations, 13 sporadic AD, and 14 control cases. Results: H-3-PIB, H-3-florbetaben, H-3-AZD2184, and BTA-1 shared a high-and a varying low-affinity binding site in the frontal cortex of sporadic AD. AZD2184 detected another binding site (affinity 33 nM) in the frontal cortex of ADAD. The H-3-AZD2184 and H-3-PIB binding were significantly higher in the striatum of ADAD compared to sporadic AD and control. Polyphenol resveratrol showed strongest inhibition on H-3-AZD84 binding followed by H-3-florbetaben and minimal on H-3-PIB. Discussion: This study implies amyloid tracers of different structures detect different sites on amyloid-beta fibrils or conformations. (C) 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.
  • Pekkala, Timo; Hall, Anette; Mangialasche, Francesca; Kemppainen, Nina; Mecocci, Patrizia; Ngandu, Tiia; Rinne, Juha O.; Soininen, Hilkka; Tuomilehto, Jaakko; Kivipelto, Miia; Solomon, Alina (2020)
    We explored the association of type 2 diabetes related blood markers with brain amyloid accumulation on PiB-PET scans in 41 participants from the FINGER PET sub-study. We built logistic regression models for brain amyloid status with12 plasma markers of glucose and lipid metabolism, controlled for diabetes and APOE epsilon 4 carrier status. Lower levels of insulin, insulin resistance index (HOMA-IR), C-peptide, and plasminogen activator (PAI-1) were associated with amyloid positive status, although the results were not significant after adjusting for multiple testing. None of the models found evidence for associations between amyloid status and fasting glucose or HbA1c.
  • Lilius, Tuomas O.; Blomqvist, Kim; Hauglund, Natalie; Liu, Guojun; Stæger, Frederik Filip; Bærentzen, Simone; Du, Ting; Ahlström, Fredrik; Backman, Janne T.; Kalso, Eija; Rauhala, Pekka V.; Nedergaard, Maiken (2019)
    Drug delivery to the central nervous system remains a major problem due to biological barriers. The blood-brainbarrier can be bypassed by administering drugs intrathecally directly to the cerebrospinal fluid (CSF). The glymphatic system, a network of perivascular spaces promoting fluid exchange between CSF and interstitial space, could be utilized to enhance convective drug delivery from the CSF to the parenchyma. Glymphatic flow is highest during sleep and anesthesia regimens that induce a slow-wave sleep-like state. Here, using mass spectrometry and fluorescent imaging techniques, we show that the clinically used alpha(2)-adrenergic agonist dexme-detomidine that enhances EEG slow-wave activity, increases brain and spinal cord drug exposure of intrathecally administered drugs in mice and rats. Using oxycodone, naloxone, and an IgG-sized antibody as relevant model drugs we demonstrate that modulation of glymphatic flow has a distinct impact on the distribution of intrathecally administered therapeutics. These findings can be exploited in the clinic to improve the efficacy and safety of intrathecally administered therapeutics.
  • Jansen, Ris E.; van der Lee, Sven J.; Gomez-Fonseca, Duber; de Rojas, Itziar; Dalmasso, Maria Carolina; Grenier-Boley, Benjamin; Zettergren, Anna; Mishra, Aniket; Ali, Muhammad; Andrade, Victor; Bellenguez, Celine; Kleineidam, Luca; Kucukali, Fahri; Sung, Yun Ju; Tesi, Niccolo; Vromen, Ellen M.; Wightman, Douglas P.; Alcolea, Daniel; Alegret, Montserrat; Alvarez, Ignacio; Amouyel, Philippe; Athanasiu, Lavinia; Bahrami, Shahram; Bailly, Henri; Belbin, Olivia; Bergh, Sverre; Bertram, Lars; Biessels, Geert Jan; Blennow, Kaj; Blesa, Rafael; Boada, Merce; Boland, Anne; Buerger, Katharina; Carracedo, Angel; Cervera-Carles, Laura; Chene, Genevieve; Claassen, Jurgen A. H. R.; Debette, Stephanie; Deleuze, Jean-Francois; de Deyn, Peter Paul; Diehl-Schmid, Janine; Djurovic, Srdjan; Dols-Icardo, Oriol; Dufouil, Carole; Duron, Emmanuelle; Duezel, Emrah; Fladby, Tormod; Fortea, Juan; Froelich, Lutz; Garcia-Gonzalez, Pablo; Garcia-Martinez, Maria; Giegling, Ina; Goldhardt, Oliver; Gobom, Johan; Grimmer, Timo; Haapasalo, Annakaisa; Hampel, Harald; Hanon, Olivier; Hausner, Lucrezia; Heilmann-Heimbach, Stefanie; Helisalmi, Seppo; Heneka, Michael T.; Hernandez, Isabel; Herukka, Sanna-Kaisa; Holstege, Henne; Jarholm, Jonas; Kern, Silke; Knapskog, Anne-Brita; Koivisto, Anne M.; Kornhuber, Johannes; Kuulasmaa, Teemu; Lage, Carmen; Laske, Christoph; Leinonen, Ville; Lewczuk, Piotr; Lleo, Alberto; de Munain, Adolfo Lopez; Lopez-Garcia, Sara; Maier, Wolfgang; Marquie, Marta; Mol, Merel O.; Montrreal, Laura; Moreno, Fermin; Moreno-Grau, Sonia; Nicolas, Gael; Nothen, Markus M.; Orellana, Adelina; Palhaugen, Lene; Papma, Janne M.; Pasquier, Florence; Perneczky, Robert; Peters, Oliver; Pijnenburg, Yolande A. L.; Popp, Julius; Posthuma, Danielle; Pozueta, Ana; Priller, Josef; Puerta, Raquel; Quintela, Ines; Ramakers, Inez; Rodriguez-Rodriguez, Eloy; Rujescu, Dan; Saltvedt, Ingvild; Sanchez-Juan, Pascual; Scheltens, Philip; Scherbaum, Norbert; Schmid, Matthias; Schneider, Anja; Selbaek, Geir; Selnes, Per; Shadrin, Alexey; Skoog, Ingmar; Soininen, Hilkka; Tarraga, Lluis; Teipel, Stefan; Tijms, Betty; Tsolaki, Magda; Van Broeckhoven, Christine; Van Dongen, Jasper; van Swieten, John C.; Vandenberghe, Rik; Vidal, Jean-Sebastien; Visser, Pieter J.; Vogelgsang, Jonathan; Waern, Margda; Wagner, Michael; Wiltfang, Jens; Wittens, Mandy M. J.; Zetterberg, Henrik; Zulaica, Miren; van Duijn, Cornelia M.; Bjerke, Maria; Engelborghs, Sebastiaan; Jessen, Frank; Teunissen, Charlotte E.; Pastor, Pau; Hiltunen, Mikko; Ingelsson, Martin; Andreassen, Ole A.; Clarimon, Jordi; Sleegers, Kristel; Ruiz, Agustin; Ramirez, Alfredo; Cruchaga, Carlos; Lambert, Jean-Charles; van der Flier, Wiesje (2022)
    Amyloid-beta 42 (A beta 42) and phosphorylated tau (pTau) levels in cerebrospinal fluid (CSF) reflect core features of the pathogenesis of Alzheimer's disease (AD) more directly than clinical diagnosis. Initiated by the European Alzheimer & Dementia Biobank (EADB), the largest collaborative effort on genetics underlying CSF biomarkers was established, including 31 cohorts with a total of 13,116 individuals (discovery n = 8074; replication n = 5042 individuals). Besides the APOE locus, novel associations with two other well-established AD risk loci were observed; CR1 was shown a locus for A beta 42 and BIN1 for pTau. GMNC and C16orf95 were further identified as loci for pTau, of which the latter is novel. Clustering methods exploring the influence of all known AD risk loci on the CSF protein levels, revealed 4 biological categories suggesting multiple A beta 42 and pTau related biological pathways involved in the etiology of AD. In functional follow-up analyses, GMNC and C16orf95 both associated with lateral ventricular volume, implying an overlap in genetic etiology for tau levels and brain ventricular volume.
  • Svarcbahs, Reinis; Julku, Ulrika; Kilpelainen, Tommi; Kyyrö, Mirva; Jäntti, Maria; Myohänen, Timo T. (2019)
    Changes in prolyl oligopeptidase (PREP) expression levels, protein distribution, and activity correlate with aging and are reported in many neurodegenerative conditions. Together with decreased neuropeptide levels observed in aging and neurodegeneration, and PREP's ability to cleave only small peptides, PREP was identified as a druggable target. Known PREP non-enzymatic functions were disregarded or attributed to PREP enzymatic activity, and several potent small molecule PREP inhibitors were developed during early stages of PREP research. These showed a lot of potential but with variable results in experimental memory models, however, the initial excitement was short-lived and all of the clinical trials were discontinued in either Phase I or II clinical trials for unknown reasons. Recently, PREP's ability to form protein-protein interactions, alter cell proliferation and autophagy has gained more attention than earlier recognized catalytical activity. Of new findings, particularly the aggregation of alpha-synuclein (aSyn) that is seen in the presence of PREP is especially interesting because PREP inhibitors are capable of altering aSyn-PREP interaction in a manner that reduces the aSyn dimerization process. Therefore, it is possible that PREP inhibitors that are altering interactions could have different characteristics than those aimed for strong inhibition of catalytic activity. Moreover, PREP co-localization with aSyn, tau, and amyloid-beta hints to PREP's possible role not only in the synucleinopathies but in other neurodegenerative diseases as well. This commentary will focus on less well-acknowledged non-enzymatic functions of PREP that may provide a better approach for the development of PREP inhibitors for the treatment of neurodegenerative disorders.