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Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.

ABSTRACT: Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque-associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss-of-function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2, early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque-associated ApoE.

SUBMITTER: Parhizkar S

PROVIDER: S-EPMC6417433 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.

Parhizkar Samira S Arzberger Thomas T Brendel Matthias M Kleinberger Gernot G Deussing Maximilian M Focke Carola C Nuscher Brigitte B Xiong Monica M Ghasemigharagoz Alireza A Katzmarski Natalie N Krasemann Susanne S Lichtenthaler Stefan F SF Müller Stephan A SA Colombo Alessio A Monasor Laura Sebastian LS Tahirovic Sabina S Herms Jochen J Willem Michael M Pettkus Nadine N Butovsky Oleg O Bartenstein Peter P Edbauer Dieter D Rominger Axel A Ertürk Ali A Grathwohl Stefan A SA Neher Jonas J JJ Holtzman David M DM Meyer-Luehmann Melanie M Haass Christian C

Nature neuroscience 20190107 2

Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late-onset Alzheimer's disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque-associated apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic a ...[more]

PMID: 30617257

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Project description:TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of ?-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2ko females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2ko brains, and the A?42:A?40 ratio was elevated. The amount of soluble, fibrillar A? oligomers also increased in PS2APP;Trem2ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of A? into dense plaque is an important neuroprotective activity.SIGNIFICANCE STATEMENT Genetic studies indicate that TREM2 gene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects of Trem2 deletion in the PS2APP mouse AD model, in which overproduction of A? peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of Trem2-deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12-22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the A?42:A?40 ratio and amount of soluble, fibrillar A? oligomers were elevated in Trem2-deficient brains. These results suggest that the Trem2-dependent compaction of A? into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic A? species.

Dataset Information

Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.

Publications

Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE.

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