Increase of TREM2 during Aging of an Alzheimer’s Disease Mouse Model Is Paralleled by Microglial Activation and Amyloidosis

Brendel, Matthias; Kleinberger, Gernot; Probst, Federico; Jaworska, Anna; Overhoff, Felix; Blume, Tanja; Albert, Nathalie L.; Carlsen, Janette; Lindner, Simon; Gildehaus, Franz Josef; Ozmen, Laurence; Suárez‐Calvet, Marc; Bartenstein, Peter; Baumann, Karlheinz; Ewers, Michael; Herms, Jochen; Haass, Christian; Rominger, Axel

doi:10.3389/fnagi.2017.00008

Cited by 62 publications

(64 citation statements)

References 46 publications

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“…The PSEN2 −/− (PS2KO) mouse line [33] was also included to check for PS2 loss-of-function defects [34]. Of these lines, at six months of age, only the B6.152H shows plaque accumulation and gliosis in the cortex and hippocampus ( Figure 1A-C), as previously reported [12], with no signs of neurodegeneration [26,27,29,33]. As shown in Figure 1D, from three to six months, there is 2-log increase in the Aβ42 level in the hippocampus of B6.152H mice, but only 1-log change in APPSwe mice, which also starts from a lower level compared to B6.152H mice.…”

Section: In Vivo Multi-site Lfp Recordings From Wt and Tg Micementioning

confidence: 64%

“…The spontaneous electrical activity of WT mice was thus compared to that of the double tg B6.152H mice, which express both the human APP-KM670/671NL (Swedish) and the PS2-N141I mutations, and show the first appearance of plaques and gliosis in the cortex and HPF at six months of age [26,27]. These mice have been studied by Positron Emission Tomography (PET) [28,29] and Magnetic Resonance Imaging (MRI) [30], as well as through pharmacological, electrophysiological, and Ca 2+ imaging approaches [12,31,32]. To identify the differences related to either the initial accumulation of Aβ or the deposition of plaques, we used mouse cohorts of three and six months of age, corresponding, respectively, to either the absence or presence of plaques and gliosis in B6.152H mice [12,26].…”

Section: Introductionmentioning

confidence: 99%

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Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

Leparulo

Mahmud

Scremin

et al. 2019

Cells

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To fight Alzheimer’s disease (AD), we should know when, where, and how brain network dysfunctions initiate. In AD mouse models, relevant information can be derived from brain electrical activity. With a multi-site linear probe, we recorded local field potentials simultaneously at the posterior-parietal cortex and hippocampus of wild-type and double transgenic AD mice, under anesthesia. We focused on PS2APP (B6.152H) mice carrying both presenilin-2 (PS2) and amyloid precursor protein (APP) mutations, at three and six months of age, before and after plaque deposition respectively. To highlight defects linked to either the PS2 or APP mutation, we included in the analysis age-matched PS2.30H and APP-Swedish mice, carrying each of the mutations individually. Our study also included PSEN2−/− mice. At three months, only predeposition B6.152H mice show a reduction in the functional connectivity of slow oscillations (SO) and in the power ratio between SO and delta waves. At six months, plaque-seeding B6.152H mice undergo a worsening of the low/high frequency power imbalance and show a massive loss of cortico-hippocampal phase-amplitude coupling (PAC) between SO and higher frequencies, a feature shared with amyloid-free PS2.30H mice. We conclude that the PS2 mutation is sufficient to impair SO PAC and accelerate network dysfunctions in amyloid-accumulating mice.

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Section: In Vivo Multi-site Lfp Recordings From Wt and Tg Micementioning

confidence: 64%

Section: Introductionmentioning

confidence: 99%

Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

Leparulo

Mahmud

Scremin

et al. 2019

Cells

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“…Normalization of injected activity was performed by the previously validated myocardium correction method (Deussing et al , ) for TSPO‐PET and by percentage of the injected dose (%‐ID) for FDG‐PET. Known changes in TSPO and FDG‐PET during aging (Brendel et al , ) were accounted to compensate for natural age differences between individual mice. Groups of Grn −/− and Trem2 −/− mice were averaged and compared against wt mice by calculation of %‐differences in each cerebral voxel.…”

Section: Methodsmentioning

confidence: 99%

Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

et al. 2019

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Microglia adopt numerous fates with homeostatic microglia ( HM ) and a microglial neurodegenerative phenotype ( MG nD) representing two opposite ends. A number of variants in genes selectively expressed in microglia are associated with an increased risk for neurodegenerative diseases such as Alzheimer's disease ( AD ) and frontotemporal lobar degeneration ( FTLD ). Among these genes are progranulin ( GRN ) and the triggering receptor expressed on myeloid cells 2 ( TREM 2 ). Both cause neurodegeneration by mechanisms involving loss of function. We have now isolated microglia from Grn −/− mice and compared their transcriptomes to those of Trem2 −/− mice . Surprisingly, while loss of Trem2 enhances the expression of genes associated with a homeostatic state, microglia derived from Grn −/− mice showed a reciprocal activation of the MG nD molecular signature and suppression of gene characteristic for HM . The opposite mRNA expression profiles are associated with divergent functional phenotypes. Although loss of TREM 2 and progranulin resulted in opposite activation states and functional phenotypes of microglia, FDG (fluoro‐2‐deoxy‐ d ‐glucose)‐μ PET of brain revealed reduced glucose metabolism in both conditions, suggesting that opposite microglial phenotypes result in similar wide spread brain dysfunction.

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“…[ 18 F]GE180 is an admirably fit tracer for TSPO imaging in glioma, a condition with BBB disruption, 140 and is a sensitive tracer for TSPO activation in rodent brain, 141 thus suggesting an important species differences in permeability of that tracer to the BBB.…”

Section: Metabolism and Plasma Protein Bindingmentioning

confidence: 99%

Sifting through the surfeit of neuroinflammation tracers

Cumming

Burgher

Patkar

et al. 2017

J Cereb Blood Flow Metab

100

113

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The first phase of molecular brain imaging of microglial activation in neuroinflammatory conditions began some 20 years ago with the introduction of [C]-( R)-PK11195, the prototype isoquinoline ligand for translocator protein (18 kDa) (TSPO). Investigations by positron emission tomography (PET) revealed microgliosis in numerous brain diseases, despite the rather low specific binding signal imparted by [C]-( R)-PK11195. There has since been enormous expansion of the repertoire of TSPO tracers, many with higher specific binding, albeit complicated by allelic dependence of the affinity. However, the specificity of TSPO PET for revealing microglial activation not been fully established, and it has been difficult to judge the relative merits of the competing tracers and analysis methods with respect to their sensitivity for detecting microglial activation. We therefore present a systematic comparison of 13 TSPO PET and single photon computed tomography (SPECT) tracers belonging to five structural classes, each of which has been investigated by compartmental analysis in healthy human brain relative to a metabolite-corrected arterial input. We emphasize the need to establish the non-displaceable binding component for each ligand and conclude with five recommendations for a standard approach to define the cellular distribution of TSPO signals, and to characterize the properties of candidate TSPO tracers.

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Increase of TREM2 during Aging of an Alzheimer’s Disease Mouse Model Is Paralleled by Microglial Activation and Amyloidosis

Cited by 62 publications

References 46 publications

Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

Dampened Slow Oscillation Connectivity Anticipates Amyloid Deposition in the PS2APP Mouse Model of Alzheimer’s Disease

Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

Sifting through the surfeit of neuroinflammation tracers

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