Alzheimer's disease risk alleles in TREM2 illuminate innate immunity in Alzheimer's disease
ABSTRACT 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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ABSTRACT: The Triggering Receptors Expressed on Myeloid cells (TREM) are a family of cell-surface molecules that control inflammation, bone homeostasis, neurological development and blood coagulation. TREM-1 and TREM-2, the best-characterized receptors so far, play divergent roles in several infectious diseases. In the intestine, TREM-1 is highly expressed by macrophages, contributing to inflammatory bowel disease (IBD) pathogenesis. Contrary to current understanding, TREM-2 also promotes inflammation in IBD by fueling dendritic cell functions. This review will focus specifically on recent insights into the role of TREM proteins in IBD development, and discuss opportunities for novel treatment approaches.Journal of Translational Medicine 10/2014; 12(1):293. DOI:10.1186/s12967-014-0293-z · 3.99 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) is the leading cause of dementia worldwide. Late-onset AD (LOAD), is the most common form of Alzheimer's disease, representing about >95% of cases and early-onset AD represents <5% of cases. Several risk factors have been discovered that are associated with AD, with advancing age being the most prominent. Other environmental risk factors include diabetes mellitus, level of physical activity, educational status, hypertension and head injury. The most well known genetic risk factor for LOAD is inheritance of the apolipoprotein (apo) E4 allele. Recently, rare variants of TREM2 have been reported as a significant risk factor for LOAD, comparable to inheritance of apoE4. In this review we will focus on the role(s) of TREM2 in AD as well as in other neurodegenerative disorders.
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ABSTRACT: Aging is the main risk factor for Alzheimer's disease (AD). With aging, inflammation has been recognized as potential trigger for starting the neurodegenerative cascade leading to neuronal death. Before Aβ and tau accumulation, evidence has put alterations of the cell cycle at the core of these processes. Still, a number of features of the cell cycle re-entry phenotype have remained elusive to the role of ectopic protein expression in the process of neuroinflammation and consequently neuronal cell death. Recently, a novel cyclin dependent kinase CDK11 has been found to be involved in astrocyte mediated inflammatory response and Alzheimer's disease. In this review, we aim to establish the missing part of the puzzle between neuroinflammation and APP / Aβ deregulation in AD by evaluating the role of a cyclin, CDK11. CDK11 may play a vital role in cell cycle re-entry in AD neurons in an APP-dependent manner, thus presenting an intriguing novel function of the APP signaling pathway in AD.