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

被引：395

作者：

Parhizkar, Samira ^{[1
]}

Arzberger, Thomas ^{[2
,3
,4
,5
]}

Brendel, Matthias ^{[6
]}

Kleinberger, Gernot ^{[1
,2
]}

Deussing, Maximilian ^{[6
]}

Focke, Carola ^{[6
]}

Nuscher, Brigitte ^{[1
]}

Xiong, Monica ^{[7
,8
]}

Ghasemigharagoz, Alireza ^{[9
]}

Katzmarski, Natalie ^{[10
,11
]}

Krasemann, Susanne ^{[12
,13
]}

Lichtenthaler, Stefan F. ^{[2
,3
,14
,15
]}

Mueller, Stephan A. ^{[3
,14
]}

Colombo, Alessio ^{[3
]}

Monasor, Laura Sebastian ^{[3
]}

Tahirovic, Sabina ^{[3
]}

Herms, Jochen ^{[2
,3
,4
]}

Willem, Michael ^{[1
]}

Pettkus, Nadine ^{[1
]}

Butovsky, Oleg ^{[12
,16
]}

Bartenstein, Peter ^{[2
,6
]}

Edbauer, Dieter ^{[2
,3
]}

Rominger, Axel ^{[2
,6
,19
]}

Ertuerk, Ali ^{[9
]}

Grathwohl, Stefan A. ^{[17
]}

Neher, Jonas J. ^{[17
,18
]}

Holtzman, David M. ^{[7
,8
]}

Meyer-Luehmann, Melanie ^{[10
,11
]}

Haass, Christian ^{[1
,2
,3
]}

机构：

[1] Ludwig Maximilians Univ Munchen, Fac Med, Biomed Ctr BMC, Chair Metab Biochem, Munich, Germany

[2] Munich Cluster Syst Neurol SyNergy, Munich, Germany

[3] German Ctr Neurodegenerat Dis DZNE Munich, Munich, Germany

[4] Ludwig Maximilians Univ Munchen, Ctr Neuropathol & Prion Res, Munich, Germany

[5] Ludwig Maximilians Univ Munchen, Dept Psychiat & Psychotherapy, Munich, Germany

[6] Ludwig Maximilians Univ Munchen, Univ Hosp, Dept Nucl Med, Munich, Germany

[7] Washington Univ, Sch Med, Dept Neurol, Hope Ctr Neurol Disorders, St Louis, MO 63110 USA

[8] Washington Univ, Sch Med, Charles F & Joanne Knight Alzheimers Dis Res Ctr, St Louis, MO USA

[9] Klinikum Univ Munchen, Inst Stroke & Dementia Res, Munich, Germany

[10] Univ Freiburg, Med Ctr, Dept Neurol, Freiburg, Germany

[11] Univ Freiburg, Fac Med, Freiburg, Germany

[12] Harvard Med Sch, Brigham & Womens Hosp, Ann Romney Ctr Neurol Dis, Dept Neurol, Boston, MA USA

[13] Univ Med Ctr Hamburg Eppendorf, Inst Neuropathol, Hamburg, Germany

[14] Tech Univ Munich, Sch Med, Klinikum Rechts Isar, Neuroprote, Munich, Germany

[15] Tech Univ Munich, Inst Adv Study, Garching, Germany

[16] Harvard Med Sch, Brigham & Womens Hosp, Evergrande Ctr Immunol Dis, Boston, MA USA

[17] Univ Tubingen, Hertie Inst Clin Brain Res, Dept Cellular Neurol, Tubingen, Germany

[18] German Ctr Neurodegenerat Dis DZNE Tubingen, Tubingen, Germany

[19] Univ Hosp Bern, Inselspital, Dept Nucl Med, Bern, Switzerland

来源：

NATURE NEUROSCIENCE | 2019年 / 22卷 / 02期

关键词：

MOUSE MODEL; MICROGLIAL RESPONSE; BETA; PROTEIN; PET; DEFICIENCY; ACTIVATION; BRAIN; TSPO; IDENTIFICATION;

D O I：

10.1038/s41593-018-0296-9

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

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.

引用

页码：191 / +

页数：16

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