Journal article
Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
The Journal of neuroscience, Vol.37(3), pp.637-647
01/18/2017
DOI: 10.1523/JNEUROSCI.2110-16.2016
PMCID: PMC5242410
PMID: 28100745
Abstract
Neuroinflammation is an important contributor to Alzheimer's disease (AD) pathogenesis, as underscored by the recent identification of immune-related genetic risk factors for AD, including coding variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2). Understanding TREM2 function promises to provide important insights into how neuroinflammation contributes to AD pathology. However, studies so far have produced seemingly conflicting results, with reports that amyloid pathology can be both decreased and increased in TREM2-deficient AD mouse models. In this study, we unify these previous findings by demonstrating that TREM2 deficiency ameliorates amyloid pathology early, but exacerbates it late in disease progression in the APPPS1–21 mouse model of AD. We also demonstrate that TREM2 deficiency decreases plaque-associated myeloid cell accumulation by reducing cell proliferation, specifically late in pathology. In addition, TREM2 deficiency reduces myeloid cell internalization of amyloid throughout pathology, but decreases inflammation-related gene transcript levels selectively late in disease progression. Together, these results suggest that TREM2 plays distinct functional roles at different stages in AD pathology. SIGNIFICANCE STATEMENT Alzheimer's disease (AD) is a devastating neurodegenerative disorder and there are currently no effective treatments that modify disease progression. However, the recent identification of genetic risk factors for AD promises to provide new insight into AD biology and possible new therapeutic targets. Among these risk factors, variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2) confer greatly elevated risk for developing the disease. We demonstrate that TREM2 deficiency has opposing effects on AD-related pathologies at early and late stages of disease progression, unifying previous work in the field. In addition, we examine how TREM2 affects the function of the brain immune cell populations in which it is expressed throughout disease progression to understand possible mechanisms underlying its differential impacts on pathology.
Details
- Title: Subtitle
- Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease
- Creators
- Taylor R. Jay - Case Western Reserve UniversityAnna M. Hirsch - Case Western Reserve UniversityMargaret L. Broihier - Case Western Reserve UniversityCrystal M. Miller - Cleveland Clinic Lerner College of MedicineLee E. Neilson - Case Western Reserve UniversityRichard M. Ransohoff - Biogen (United States)Bruce T. Lamb - Case Western Reserve UniversityGary E. Landreth - Case Western Reserve University
- Resource Type
- Journal article
- Publication Details
- The Journal of neuroscience, Vol.37(3), pp.637-647
- DOI
- 10.1523/JNEUROSCI.2110-16.2016
- PMID
- 28100745
- PMCID
- PMC5242410
- NLM abbreviation
- J Neurosci
- ISSN
- 0270-6474
- eISSN
- 1529-2401
- Publisher
- Society for Neuroscience
- Number of pages
- 11
- Grant note
- Alzheimer's Association: BFG-15-364590 Jane and Lee Seidman FundNational Institute on Aging-National Institutes of Health (NIA): RF1 AG051495, R01 AG050597, F31 AG048704 Case Western Reserve University: T32 NS067431
This work was supported by the Alzheimer's Association (Grant BFG-15-364590 to G.E.L.), the Jane and Lee Seidman Fund, generous donations from Chet and Jane Scholtz and Dave and Susan Roberts (B.T.L.), the National Institute on Aging-National Institutes of Health (NIA Grant RF1 AG051495 to B.T.L. and G.E.L.; NIA Grant R01 AG050597 to G.E.L.; and NIA National Research Service Award F31 AG048704 to T.R.J.), and Case Western Reserve University (Neurosciences Training Grant T32 NS067431 to T.R.J.). We thank the imaging core at Case Western Reserve University and the flow cytometry core at the Cleveland Clinic Lerner Research Institute for technical support.
- Language
- English
- Date published
- 01/18/2017
- Academic Unit
- Neurology; Iowa Neuroscience Institute; Neuroscience and Pharmacology
- Record Identifier
- 9985089126802771
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