title: Increase of TREM2 during Aging of an Alzheimer's Disease Mouse Model Is Paralleled by Microglial Activation and Amyloidosis.
abstract: Heterozygous missense mutations in the triggering receptor expressed on myeloid cells 2 (TREM2) have been reported to significantly increase the risk of developing Alzheimer's disease (AD). Since TREM2 is specifically expressed by microglia in the brain, we hypothesized that soluble TREM2 (sTREM2) levels may increase together within vivobiomarkers of microglial activity and amyloidosis in an AD mouse model as assessed by small animal positron-emission-tomography (μPET). In this cross-sectional study, we examined a strong amyloid mouse model (PS2APP) of four age groups by μPET with [18F]-GE180 (glial activation) and [18F]-florbetaben (amyloidosis), followed by measurement of sTREM2 levels and amyloid levels in the brain. Pathology affected brain regions were compared between tracers (dice similarity coefficients) and pseudo-longitudinally. μPET results of both tracers were correlated with terminal TREM2 levels. The brain sTREM2 levels strongly increased with age of PS2APP mice (5 vs. 16 months: +211%,p< 0.001), and correlated highly with μPET signals of microglial activity (R= 0.89,p< 0.001) and amyloidosis (R= 0.92,p< 0.001). Dual μPET enabled regional mapping of glial activation and amyloidosis in the mouse brain, which progressed concertedly leading to a high overlap in aged PS2APP mice (dice similarity 67%). Together, these results substantiate the use ofin vivoμPET measurements in conjunction with post mortem sTREM2 in future anti-inflammatory treatment trials. Taking human data into account sTREM2 may increase during active amyloid deposition.
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität München Munich, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Brendel
authors.affiliation: Department of Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians-Universität MünchenMunich, Germany; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität MünchenMunich, Germany.
authors.forename: Gernot
authors.initials: G
authors.lastname: Kleinberger
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität München Munich, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Probst
authors.affiliation: DZNE-German Center for Neurodegenerative DiseasesMunich, Germany; Laboratory of Neurodegeneration, International Institute of Molecular and Cell BiologyWarsaw, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Jaworska
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität München Munich, Germany.
authors.forename: Felix
authors.initials: F
authors.lastname: Overhoff
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität München Munich, Germany.
authors.forename: Tanja
authors.initials: T
authors.lastname: Blume
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität München Munich, Germany.
authors.forename: Nathalie L
authors.initials: NL
authors.lastname: Albert
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität München Munich, Germany.
authors.forename: Janette
authors.initials: J
authors.lastname: Carlsen
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität München Munich, Germany.
authors.forename: Simon
authors.initials: S
authors.lastname: Lindner
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität München Munich, Germany.
authors.forename: Franz Josef
authors.initials: FJ
authors.lastname: Gildehaus
authors.affiliation: Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. Basel, Switzerland.
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.affiliation: Department of Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians-Universität MünchenMunich, Germany; DZNE-German Center for Neurodegenerative DiseasesMunich, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Suárez-Calvet
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität MünchenMunich, Germany; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität MünchenMunich, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Bartenstein
authors.affiliation: Roche Pharma Research and Early Development, Neuroscience Discovery, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd. Basel, Switzerland.
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
authors.affiliation: DZNE-German Center for Neurodegenerative Diseases Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Ewers
authors.affiliation: Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität MünchenMunich, Germany; DZNE-German Center for Neurodegenerative DiseasesMunich, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Herms
authors.affiliation: Department of Biochemistry, Biomedical Center (BMC), Ludwig-Maximilians-Universität MünchenMunich, Germany; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität MünchenMunich, Germany; DZNE-German Center for Neurodegenerative DiseasesMunich, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Haass
authors.affiliation: Department of Nuclear Medicine, Ludwig-Maximilians-Universität MünchenMunich, Germany; Munich Cluster for Systems Neurology (SyNergy), Ludwig-Maximilians-Universität MünchenMunich, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Rominger
keywords: Alzheimer’s disease; TREM2; TSPO-PET; amyloid-PET; neuroinflammation