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TSPO alzheimer

Akshay Nair, Mattia Veronese, Xiaohui Xu, Charles Curtis, Federico Turkheimer, Robert Howard, Suzanne Reeves
PURPOSE: In order to maximise the utility of [(11)C]-PBR28 for use in longitudinal studies and clinical trials in Alzheimer's disease (AD), there is a need to develop non-invasive metrics of tracer binding that do not require arterial cannulation. Recent work has suggested that standardised uptake value (SUV)-based methods may be sensitive to changes in translocator protein (TSPO) levels associated with neurodegeneration. However, the test-retest reliability of these approaches in AD over a time period relevant for clinical trials is unknown...
December 2016: EJNMMI Research
Aurélie Doméné, Chelsea Cavanagh, Guylène Page, Sylvie Bodard, Christophe Klein, Cécile Delarasse, Sylvie Chalon, Slavica Krantic
Recent mouse studies of the presymptomatic stage of Alzheimer's disease (AD) have suggested that proinflammatory changes, such as glial activation and cytokine induction, may occur already at this early stage through unknown mechanisms. Because TNFα contributes to increased Aβ production from the Aβ precursor protein (APP), we assessed a putative correlation between APP/Aβ and TNFα during the presymptomatic stage as well as early astrocyte activation in the hippocampus of 3-month-old APPswe/PS1dE9 mice...
2016: International Journal of Alzheimer's Disease
Anna M Barron, Masaki Tokunaga, Ming-Rong Zhang, Bin Ji, Tetsuya Suhara, Makoto Higuchi
BACKGROUND: Obesity has been identified as a risk factor for cognitive decline and Alzheimer's disease (AD). The aim of this study was to investigate the effect of obesity on neuroinflammation and cerebral glucose metabolism using PET in a mouse model of β-amyloidosis and determine the relationship between these PET imaging biomarkers, pathogenic changes, and functional outcomes. METHODS: Three-month-old C57BL/J6 mice were fed either a standard (control group) or high-fat diet (obese group) for 3 months and intracerebroventricularly infused with vehicle or human beta amyloid 1-42 (Aβ42)...
2016: Journal of Neuroinflammation
William C Kreisl, Chul Hyoung Lyoo, Jeih-San Liow, Monica Wei, Joseph Snow, Emily Page, Kimberly J Jenko, Cheryl L Morse, Sami S Zoghbi, Victor W Pike, R Scott Turner, Robert B Innis
This longitudinal study sought to determine whether the 18 kDa translocator protein (TSPO), a marker of neuroinflammation, increases over time in Alzheimer's disease. Positron emission tomography imaging with the TSPO radioligand (11)C-PBR28 was performed at baseline and after a median follow-up of 2.7 years in 14 amyloid-positive patients and 8 amyloid-negative controls. Patients had a greater increase in TSPO binding than controls in inferior parietal lobule, precuneus, occipital cortex, hippocampus, entorhinal cortex, and combined middle and inferior temporal cortex...
August 2016: Neurobiology of Aging
Sandeep Sv Golla, Ronald Boellaard, Vesa Oikonen, Anja Hoffmann, Bart N M van Berckel, Albert D Windhorst, Jere Virta, Erik T Te Beek, Geert Jan Groeneveld, Merja Haaparanta-Solin, Pauliina Luoto, Nina Savisto, Olof Solin, Ray Valencia, Andrea Thiele, Jonas Eriksson, Robert C Schuit, Adriaan A Lammertsma, Juha Rinne
: Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ((18)F-DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of (18)F-DPA-714 binding. METHODS: Ninety minutes dynamic (18)F-DPA-714 positron emission tomography scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer's disease (AD) patients were used...
June 3, 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Masamichi Yokokura, Tatsuhiro Terada, Tomoyasu Bunai, Kyoko Nakaizumi, Kiyokazu Takebayashi, Yasuhide Iwata, Etsuji Yoshikawa, Masami Futatsubashi, Katsuaki Suzuki, Norio Mori, Yasuomi Ouchi
The presence of activated microglia in the brains of healthy elderly people is a matter of debate. We aimed to clarify the degree of microglial activation in aging and dementia as revealed by different tracers by comparing the binding potential (BPND) in various brain regions using a first-generation translocator protein (TSPO) tracer [(11)C](R)PK11195 and a second-generation tracer [(11)C]DPA713. The BPND levels, estimated using simplified reference tissue models, were compared among healthy young and elderly individuals and patients with Alzheimer's disease (AD) and were correlated with clinical scores...
April 26, 2016: Journal of Cerebral Blood Flow and Metabolism
Fei Li, Jian Liu, Nan Liu, Leslie A Kuhn, R Michael Garavito, Shelagh Ferguson-Miller
Translocator protein 18 kDa (TSPO) was previously known as the peripheral benzodiazepine receptor (PBR) in eukaryotes, where it is mainly localized to the mitochondrial outer membrane. Considerable evidence indicates that it plays regulatory roles in steroidogenesis and apoptosis and is involved in various human diseases, such as metastatic cancer, Alzheimer's and Parkinson's disease, inflammation, and anxiety disorders. Ligands of TSPO are widely used as diagnostic tools and treatment options, despite there being no clear understanding of the function of TSPO...
May 24, 2016: Biochemistry
Nazanin Mirzaei, Sac Pham Tang, Sharon Ashworth, Christopher Coello, Christophe Plisson, Jan Passchier, Vimal Selvaraj, Robin J Tyacke, David J Nutt, Magdalena Sastre
Microglial activation has been linked with deficits in neuronal function and synaptic plasticity in Alzheimer's disease (AD). The mitochondrial translocator protein (TSPO) is known to be upregulated in reactive microglia. Accurate visualization and quantification of microglial density by PET imaging using the TSPO tracer [(11)C]-R-PK11195 has been challenging due to the limitations of the ligand. In this study, it was aimed to evaluate the new TSPO tracer [(11)C]PBR28 as a marker for microglial activation in the 5XFAD transgenic mouse model of AD...
June 2016: Glia
Matthias Brendel, Federico Probst, Anna Jaworska, Felix Overhoff, Viktoria Korzhova, Nathalie L Albert, Roswitha Beck, Simon Lindner, Franz-Josef Gildehaus, Karlheinz Baumann, Peter Bartenstein, Gernot Kleinberger, Christian Haass, Jochen Herms, Axel Rominger
UNLABELLED: Amyloid imaging by small-animal PET in models of Alzheimer disease (AD) offers the possibility to track amyloidogenesis and brain energy metabolism. Because microglial activation is thought to contribute to AD pathology, we undertook a triple-tracer small-animal PET study to assess microglial activation and glucose metabolism in association with amyloid plaque load in a transgenic AD mouse model. METHODS: Groups of PS2APP and C57BL/6 wild-type mice of various ages were examined by small-animal PET...
June 2016: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Li Ma, Hui Zhang, Na Liu, Pei-Qi Wang, Wen-Zhi Guo, Qiang Fu, Lin-Bo Jiao, Ya-Qun Ma, Wei-Dong Mi
Translocator protein 18kDa (TSPO) is now an attractive drug target for controlling neuroinflammation. Studies applying TSPO ligands to neurodegenerative diseases, especially Alzheimer's disease (AD), were rare. Our study was aimed to evaluate the effect of PK11195, a specific TSPO ligand, in an animal model of neuroinflammation caused by systemic LPS administration. C57/BL6 mice were treated with lipopolysaccharide (LPS, 500μg/kg, i.p.) three days after PK11195 administration (3mg/kg, i.p.). The drugs were not discontinued until the mice were sacrificed...
March 2016: Brain Research Bulletin
Daniel Felsky, Philip L De Jager, Julie A Schneider, Konstantinos Arfanakis, Debra A Fleischman, Zoe Arvanitakis, William G Honer, Jennie G Pouget, Romina Mizrahi, Bruce G Pollock, James L Kennedy, David A Bennett, Aristotle N Voineskos
The translocator protein, a microglial-expressed marker of neuroinflammation, has been implicated in Alzheimer's disease, which is characterized by alterations in vascular and inflammatory states. ATSPOvariant, rs6971, determines binding affinity of exogenous radioligandsin vivo; however, the effect of these altered binding characteristics on inflammatory and cerebrovascular biomarkers has not been assessed. In 2345 living subjects (Alzheimer's Disease Neuroimaging Initiative, n = 1330) and postmortem brain samples (Religious Orders Study and Memory and Aging Project, n = 1015), we analyzed effects of rs6971 on white matter hyperintensisites, cerebral infarcts, circulating inflammatory biomarkers, amyloid angiopathy, and microglial activation...
April 2016: Journal of Cerebral Blood Flow and Metabolism
P Porcu, A M Barron, C A Frye, A A Walf, S-Y Yang, X-Y He, A L Morrow, G C Panzica, R C Melcangi
Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic effects, mainly through interaction with the GABAA receptor. They also exert neuroprotective, neurotrophic and antiapoptotic effects in several animal models of neurodegenerative diseases...
February 2016: Journal of Neuroendocrinology
Bieneke Janssen, Danielle J Vugts, Uta Funke, Ger T Molenaar, Perry S Kruijer, Bart N M van Berckel, Adriaan A Lammertsma, Albert D Windhorst
Neuroinflammation is thought to play a pivotal role in many diseases affecting the brain, including Alzheimer's disease, multiple sclerosis and stroke. Neuroinflammation is characterised predominantly by microglial activation, which can be visualised using positron emission tomography (PET). Traditionally, translocator protein 18kDa (TSPO) is the target for imaging of neuroinflammation using PET. In this review, recent preclinical and clinical research using PET in Alzheimer's disease, multiple sclerosis and stroke is summarised...
March 2016: Biochimica et Biophysica Acta
Bin Liu, Kevin X Le, Mi-Ae Park, Shuyan Wang, Anthony P Belanger, Shipra Dubey, Jeffrey L Frost, Peter Holton, Vladimir Reiser, Paul A Jones, William Trigg, Marcelo F Di Carli, Cynthia A Lemere
UNLABELLED: Alzheimer's disease (AD) is the most common cause of dementia. Neuroinflammation appears to play an important role in AD pathogenesis. Ligands of the 18 kDa translocator protein (TSPO), a marker for activated microglia, have been used as positron emission tomography (PET) tracers to reflect neuroinflammation in humans and mouse models. Here, we used the novel TSPO-targeted PET tracer (18)F-GE180 (flutriciclamide) to investigate differences in neuroinflammation between young and old WT and APP/PS1dE9 transgenic (Tg) mice...
November 25, 2015: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Mariusz Jaremko, Łukasz Jaremko, Garima Jaipuria, Stefan Becker, Markus Zweckstetter
The 3D structure of the 18-kDa transmembrane (TM) protein TSPO (translocator protein)/PBR (peripheral benzodiazepine receptor), which contains a binding site for benzodiazepines, is important to better understand its function and regulation by endogenous and synthetic ligands. We have recently determined the structure of mammalian TSPO/PBR in complex with the diagnostic ligand PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide; Jaremko et al. (2014) Science 343: , 1363-1366], providing for the first time atomic-level insight into the conformation of this protein, which is up-regulated in various pathological conditions including Alzheimer's disease and Parkinson's disease...
August 2015: Biochemical Society Transactions
James Stefaniak, John O'Brien
We are still very limited in management strategies for dementia, and establishing effective disease modifying therapies based on amyloid or tau remains elusive. Neuroinflammation has been increasingly implicated as a pathological mechanism in dementia and demonstration that it is a key event accelerating cognitive or functional decline would inform novel therapeutic approaches, and may aid diagnosis. Much research has therefore been done to develop technology capable of imaging neuroinflammation in vivo. The authors performed a systematic search of the literature and found 28 studies that used in vivo neuroimaging of one or more markers of neuroinflammation on human patients with dementia...
January 2016: Journal of Neurology, Neurosurgery, and Psychiatry
Bin Ji, Chun-Jen Chen, Kazunori Bando, Hiroki Ashino, Hideaki Shiraishi, Hiroaki Sano, Hiroyuki Kasahara, Takao Minamizawa, Kazutaka Yamada, Maiko Ono, Ming-Rong Zhang, Chie Seki, Lars Farde, Tetsuya Suhara, Makoto Higuchi
Non-invasive determination of amyloid-β peptide (Aβ) deposition with radioligands serves for the early diagnosis and clarification of pathogenetic mechanisms of Alzheimer's disease (AD). The polymorphic binding site on multimeric Aβ for current radioligands, however, is little understood. In this study, we investigated the binding of several radioligands including (11)C-Pittsburgh Compound B ((11)C-PiB), (3)H-AZD2184, and two recently developed compounds, (125)I-DRM106 and (125)I-DRK092, with unique presubicular Aβ deposits lacking interaction with the commonly used amyloid dyes FSB...
December 2015: Journal of Neurochemistry
Rea Pihlaja, Jatta Takkinen, Olli Eskola, Jenni Vasara, Francisco R López-Picón, Merja Haaparanta-Solin, Juha O Rinne
BACKGROUND: Recently, the role of monoacylglycerol lipase (MAGL) as the principal regulator of simultaneous prostaglandin synthesis and endocannabinoid receptor activation in the CNS was demonstrated. To expand upon previously published research in the field, we observed the effect of the MAGL inhibitor JZL184 during the early-stage proinflammatory response and formation of beta-amyloid (Aβ) in the Alzheimer's disease mouse model APdE9. We also investigated its effects in proinflammatory agent - induced astrocytes and microglia isolated from adult mice...
2015: Journal of Neuroinflammation
Zhen Fan, Denise Harold, Giuseppe Pasqualetti, Julie Williams, David J Brooks, Paul Edison
UNLABELLED: Neuroinflammation plays a significant role in Alzheimer disease (AD), and translocator protein (TSPO) PET imaging allows us to quantify this process. However, the binding of second-generation TSPO tracers depends on the TSPO genotype coded by the rs6971 single-nucleotide polymorphism, with a 40%-50% increase in BP in high-affinity binders (HABs) compared with mixed-affinity binders (MABs), whereas low-affinity binders (LABs) are unsuitable for evaluation. Hence, several studies are using either HAB alone or HAB and MAB subjects...
May 2015: Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine
Kristoffer Sahlholm, Fan Liao, David M Holtzman, Jinbin Xu, Robert H Mach
The sigma-2 receptor is a steroid-binding membrane-associated receptor which has been implicated in cell survival. Sigma-2 has recently been shown to bind amyloid-β (Aβ) oligomers in Alzheimer's disease (AD) brain. Furthermore, blocking this interaction was shown to prevent or reverse the effects of Aβ to cause cognitive impairment in mouse models and synaptic loss in neuronal cultures. In the present work, the density of sigma-2 receptors was measured in a double transgenic mouse model of amyloid-β deposition (APP/PS1)...
May 1, 2015: Biochemical and Biophysical Research Communications
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