Alzheimer's disease risk alleles in TREM2 illuminate innate immunity in Alzheimer's disease

Center for Translational Research in Neurodegenerative Disease, Department of Neuroscience, McKnight Brain Institute, College of Medicine, University of Florida, Gainesville, FL 32610, USA. .
Alzheimer's Research and Therapy (Impact Factor: 3.98). 05/2013; 5(3):24. DOI: 10.1186/alzrt178
Source: PubMed


Genetic studies have provided the best evidence for cause and effect relationships in Alzheimer's disease (AD). Indeed, the identification of deterministic mutations in the APP, PSEN1 and PSEN2 genes and subsequent preclinical studies linking these mutations to alterations in Aβ production and aggregation have provided pivotal support for the amyloid cascade hypothesis. In addition, genetic, pathologic and biological studies of APOE have also indicated that the genetic risk for AD associated with APOE4 can be attributed, at least in part, to its pro-amyloidogenic effect on Aβ. In recent years a number of SNPs that show unequivocal genome-wide association with AD risk have implicated novel genetic loci as modifiers of AD risk. However, the functional implications of these genetic associations are largely unknown. For almost all of these associations, the functional variants have not been identified. Very recently, two large consortiums demonstrated that rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene confer significant risk for AD. TREM2 is a type 1 membrane receptor protein primarily expressed on microglia in the central nervous system that has been shown to regulate phagocytosis and activation of monocytes. Previously it had been shown that homozygous loss of function mutations in TREM2 cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL, Nasu Hakola disease) and also a pure form of early-onset dementia. The association of TREM2 variants with AD brings innate immune signaling into the light, affirming innate immunity's role as a significant factor in AD pathogenesis.

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Available from: Paramita Chakrabarty, Sep 20, 2014
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    • "Additional variants including D87N and T96K have been linked to AD development [1] and two other point mutations in TREM-2 (Y38C and T66M) have been linked to the development of frontotemporal dementia (FTD) [8] [9] [10] [11]. These findings highlight a crucial homeostatic role for TREM2 in maintaining neuronal health and represent the first molecular link between innate inflammatory signaling and neurodegenerative diseases [12]. However, it is currently unknown how these mutations affect TREM-2 function and thereby contribute to neurodegenerative disease pathogenesis. "
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    ABSTRACT: allow structural and biophysical study of disease-linked TREM-2 mutations. TREM-2 (triggering receptor expressed on myeloid cells- 2) is an innate immune receptor expressed on dendritic cells, macrophages, osteoclasts, and microglia. Recent genetic studies have reported the occurrence of point mutations in TREM-2 that correlate with a dramatically increased risk for the development of neurodegenerative diseases, including Alzheimer’s disease, frontotemporal dementia, and Parkinson’s disease. Structural and biophysical studies of wild-type and mutant TREM-2 ectodomains are required to understand the functional consequences of these mutations. In order to facilitate these studies, we undertook the production and crystallization of these proteins. Here we demonstrate that, unlike many single Ig domain proteins, TREM-2 could not be readily refolded from bacterially-expressed inclusion bodies. Instead, we developed a mammalian-cell based expression system for the successful production of wild-type and mutant TREM-2 proteins in milligram quantities and a single-chromatography-step purification scheme that produced diffraction-quality crystals. These crystals diffract to a resolution of 3.3 Å and produce data sufficient for structure determination. We describe herein the procedures to produce wild-type and mutant human TREM-2 Ig domains in sufficient quantities for structural and biophysical studies. Such studies are crucial to understand the functional consequences of TREM-2 point mutations linked to the development of neurodegenerative diseases and, ultimately, to develop patient-specific molecular therapies to treat them.
    Protein Expression and Purification 04/2014; 96. DOI:10.1016/j.pep.2014.01.015 · 1.70 Impact Factor
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    • "Conversely reduction of TREM2 expression by either RNA interference or by targeted gene deletion amplified inflammatory cytokine responses by macrophages following stimulation of multiple different TLRs including TLR2, 4, and 9 [26]. Hence, it has been speculated that TREM2 has a protective role in AD pathogenesis; its anti-inflammatory properties could reduce inflammation-induced innocent bystander neuronal damage [8] [16] [17]. In addition to the anti-inflammatory roles of TREM2, it is also known to effect phagocytosis of damaged/apoptotic cells. "
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    ABSTRACT: Alzheimer's disease (AD) is the leading cause for dementia in the world. It is characterized by two biochemically distinct types of protein aggregates: amyloid β (A β ) peptide in the forms of parenchymal amyloid plaques and congophilic amyloid angiopathy (CAA) and aggregated tau protein in the form of intraneuronal neurofibrillary tangles (NFT). Several risk factors have been discovered that are associated with AD. The most well-known genetic risk factor for late-onset AD is apolipoprotein E4 (ApoE4) (Potter and Wisniewski (2012), and Verghese et al. (2011)). Recently, it has been reported by two groups independently that a rare functional variant (R47H) of TREM2 is associated with the late-onset risk of AD. TREM2 is expressed on myeloid cells including microglia, macrophages, and dendritic cells, as well as osteoclasts. Microglia are a major part of the innate immune system in the CNS and are also involved in stimulating adaptive immunity. Microglia express several Toll-like receptors (TLRs) and are the resident macrophages of the central nervous system (CNS). In this review, we will focus on the recent advances regarding the role of TREM2, as well as the effects of TLRs 4 and 9 on AD.
    International Journal of Cell Biology 10/2013; 2013(10):576383. DOI:10.1155/2013/576383
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    Frontiers in Cellular Neuroscience 08/2013; 7:131. DOI:10.3389/fncel.2013.00131 · 4.29 Impact Factor
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