Mice were fasted overnight for 16? h prior to sample collection. 1-42 (A42). We assessed obesity-induced abnormalities in peripheral metabolic indices including adiposity, fasting glucose, and glucose tolerance. Brain glucose metabolism was assessed by 18F-FDG PET, and glial activation was assessed using the translocator protein (TSPO) ligand 11C-PBR-28. TSPO expression was confirmed by immunohistochemistry of brain sections obtained from scanned mice. The association between inflammatory state and IV-23 11C-PBR-28 PET signals was characterized by examination of the cytokine expression profile in both the serum and hippocampus by antibody array. Learning and memory performance IV-23 was assessed in the object recognition task, and anxiety-related behavior was assessed in the elevated plus maze. Results Obesity combined with A infusion promoted neuroinflammation and cerebral hypermetabolism, and these signals were significant predictors of learning and memory overall performance in the object acknowledgement task. In vivo TSPO signals were associated with inflammatory markers including Mouse Monoclonal to Rabbit IgG (kappa L chain) CXCL1, CXCL2, CXCL12, CCL3, CCL5, TIMP-1, G-CSF, sICAM-1, and IL-1ra. Conclusions In vivo cerebral metabolism and TSPO signals indicate that obesity can accelerate amyloid-induced inflammation and associated cognitive decline. for induction, 1.5?% for maintenance), positioned in a stereotaxic apparatus and 0.9?% saline applied to the eyes. The scalp was shaved and cut, the skull uncovered, and adhering tissue was removed with acetone. A cannula (Brain Infusion Kit 3, Alzet) was implanted in the left ventricle at the following coordinates: +1.0 medial/lateral, ?0.3 anterior/posterior, ?2.5 dorsal/ventral. The cannula was fixed to the skull using dental cement and connected to a mini-osmotic pump (Model 1002, Alzet) that was filled with either vehicle (250?g/mL high-density lipoprotein (HDL) IV-23 in 4?mM HEPES with 2.5?% DMSO) or 120-M oligomeric A-42 . Oligomeric A-42 was prepared by solubilizing synthetic human A-42 (Peptide Institute) to 1 1?mM in hexafluoroisopropanol, then drying under vacuum in a SpeedVac. The peptide film was then resuspended in DMSO to 5?mM and diluted in 4?mM HEPES containing 250?g/mL HDL (Millipore) to a final concentration of 120?M. Pumps were partially coated with paraffin to adjust the infusion rate to 3?L/day for 1?month, then the filled pumps were incubated in sterile phosphate-buffered saline (PBS) at 37?C for 40?h prior to implantation under the dorsal skin on the back. The incision site around the scalp was closed with suture, and mice were administered buprenorphrine (0.05?mg/kg?i.p., Henry Schein Inc.) post-operatively for analgesia. One spontaneous death occurred in the 8?weeks post-surgery treatment period (obese?+?A group). All experimentation was carried out in strict accordance with the recommendations in the Guideline for the Care and Use of Laboratory Animals of the National Institutes of Health and was approved by the Institutional Animal Care and Use Committee of the National Institutes for Quantum and Radiological Science and Technology, Japan. Glucose measurements Fasting blood glucose was assessed using a Nipro Freestyle Glucometer (Nipro Diagnostics, Florida, USA) from the whole blood collected via the tail vein while the mouse was under isofluorane general anesthesia. Mice were fasted overnight for 16?h prior to sample collection. Mice were fasted at baseline (time 0), 1, 2?months and sacrificed for assessment of blood glucose levels. Mice were additionally fasted overnight at 2.5?months for the 18F-FDG PET scans and again for 2? days later for the glucose tolerance test. For the glucose tolerance test, baseline glucose levels were measured, then fasted mice were injected with 2?mg glucose/g body weight (i.p.), and blood glucose was measured from the whole blood collected via the tail vein 30, 60, and 120?min after injection. In vivo PET imaging TSPO signals were assessed by PET using 11C-PBR-28, which was prepared according to previously published methods . The specific activity of the end product was 80.7??14.7?GBq/mol and the radiochemical purity exceeded 95?%. 18F-FDG was purchased from Nihon Medi-Physics Co. LTD (Tokyo, Japan). Mice were fasted prior to 18F-FDG PET scans, and blood glucose levels were assessed at the completion of scan. Mice were anesthetized with 1.5?% (MRI slices of the mouse brain indicating the hippocampal (Hp), cerebellar (Cb), and lesion-site (Lesion) VOIs utilized for PET quantification Behavioral assessment Short-term working memory was assessed in the object recognition task. Mice were placed in the centre of an open field (50??50??50?cm) and allowed to freely explore for 3?min (habituation trial). Following a 2-h interval, mice were again placed in the centre of the maze between two identical objects and allowed to explore freely for 6?min (training trial). The frequency of the left and right IV-23 object explorations were scored to test for spatial bias. After a 24-h inter-trial interval, one object was replaced with a novel object and the mouse was allowed to freely explore for 10?min (probe trial). The duration of novel (extending into the dorsal hippocampus (indicated by unstandardized coefficients, standardized coefficients, tissue inhibitor of metalloproteinases, macrophage colony-stimulating factor, interleukin 2, granulocyte colony-stimulating factor, interleukin 1 receptor antagonist, interleukin 6, intracellular adhesion molecule.