BACKGROUND:
Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia.
METHODS:
We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alzheimer's disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer's disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alzheimer's disease and in control mice.
RESULTS:
We found significantly more variants in exon 2 of TREM2 in patients with Alzheimer's disease than in controls in the discovery set (P=0.02). There were 22 variant alleles in 1092 patients with Alzheimer's disease and 5 variant alleles in 1107 controls (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alzheimer's disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P=0.002), as did direct genotyping of an additional series of 1887 patients with Alzheimer's disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alzheimer's disease.
CONCLUSIONS:
Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alzheimer's disease. (Funded by Alzheimer's Research UK and others.).

/pdf/trem2-variants-in-alzheimer-s-disease-2ezeh2dex3.pdf

TREM2 Variants in Alzheimer's Disease

http://sdcsb.ucsd.edu/wp-content/uploads/2013/10/Cell2013.Zhang_.pdf

Integrated Systems Approach Identifies Genetic Nodes and Networks in Late-Onset Alzheimer’s Disease

The concept of multiple macrophage activation states is not new. However, extending this idea to resident tissue macrophages, like microglia, has gained increased interest in recent years. Unfortunately, the research on peripheral macrophage polarization does not necessarily translate accurately to their central nervous system (CNS) counterparts. Even though pro- and anti-inflammatory cytokines can polarize microglia to distinct activation states, the specific functions of these states is still an area of intense debate. This review examines the multiple possible activation states microglia can be polarized to. This is followed by a detailed description of microglial polarization and the functional relevance of this process in both acute and chronic CNS disease models described in the literature. Particular attention is given to utilizing M2 microglial polarization as a potential therapeutic option in treating diseases.

/pdf/neuroinflammation-and-m2-microglia-the-good-the-bad-and-the-hw4av38cgd.pdf

Neuroinflammation and M2 microglia: the good, the bad, and the inflamed.

Proliferation and activation of microglia in the brain, concentrated around amyloid plaques, is a prominent feature of Alzheimer’s disease (AD). Human genetics data point to a key role for microglia in the pathogenesis of AD. The majority of risk genes for AD are highly expressed (and many are selectively expressed) by microglia in the brain. There is mounting evidence that microglia protect against the incidence of AD, as impaired microglial activities and altered microglial responses to β-amyloid are associated with increased AD risk. On the other hand, there is also abundant evidence that activated microglia can be harmful to neurons. Microglia can mediate synapse loss by engulfment of synapses, likely via a complement-dependent mechanism; they can also exacerbate tau pathology and secrete inflammatory factors that can injure neurons directly or via activation of neurotoxic astrocytes. Gene expression profiles indicate multiple states of microglial activation in neurodegenerative disease settings, which might explain the disparate roles of microglia in the development and progression of AD pathology.

/pdf/microglia-in-alzheimer-s-disease-4edri8sjir.pdf

Microglia in Alzheimer's disease.

https://www.cell.com/cell/pdf/S0092-8674(15)00127-0.pdf

TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model

A b s t r ac t Background Homozygous loss-of-function mutations in TREM2, encoding the triggering receptor expressed on myeloid cells 2 protein, have previously been associated with an autosomal recessive form of early-onset dementia. Methods We used genome, exome, and Sanger sequencing to analyze the genetic variability in TREM2 in a series of 1092 patients with Alz hei mer’s disease and 1107 controls (the discovery set). We then performed a meta-analysis on imputed data for the TREM2 variant rs75932628 (predicted to cause a R47H substitution) from three genomewide association studies of Alzheimer’s disease and tested for the association of the variant with disease. We genotyped the R47H variant in an additional 1887 cases and 4061 controls. We then assayed the expression of TREM2 across different regions of the human brain and identified genes that are differentially expressed in a mouse model of Alz hei mer’s disease and in control mice. Results We found significantly more variants in exon 2 of TREM2 in patients with Alz heimer’s disease than in controls in the discovery set (P = 0.02). There were 22 variant alleles in 1092 patients with Alz hei mer’s disease and 5 variant alleles in 1107 con trols (P<0.001). The most commonly associated variant, rs75932628 (encoding R47H), showed highly significant association with Alz hei mer’s disease (P<0.001). Meta-analysis of rs75932628 genotypes imputed from genomewide association studies confirmed this association (P = 0.002), as did direct genotyping of an addi tional series of 1887 patients with Alz hei mer’s disease and 4061 controls (P<0.001). Trem2 expression differed between control mice and a mouse model of Alz hei mer’s disease. Conclusions Heterozygous rare variants in TREM2 are associated with a significant increase in the risk of Alz hei mer’s disease. (Funded by Alz hei mer’s Research UK and others.)

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1211851

TREM2 Variants in Alz hei mer's Disease

Spinocerebellar ataxia type 2 (SCA2) has been recognized recently as an uncommon cause of parkinsonism, an alternate presentation to the typical cerebellar disorder. This research review summarizes the existing literature on parkinsonism-predominant presentation SCA2 and presents new clinical cases of patients with this condition. Various phenotypes are noted in this subtype of SCA2, including parkinsonism indistinguishable from idiopathic Parkinson's disease (PD), parkinsonism plus ataxia, motor neuron disease, and postural tremor. In several kindreds with multiple affected family members, the SCA2 expansion segregated with disease; in addition, several single cases of parkinsonism with and without a family history are also described. The number of repeats in symptomatic patients ranged from 33 to 43. Interruption of the CAG repeat with CAA, CGG, or CCG was found in some individuals, possibly stabilizing the repeat structure and accounting for the relative stability of the repeat size across generations in some families; allele length is not necessarily indicative of trinucleotide repeat architecture. Positron emission tomography scanning in one family showed reduced fluorodopa uptake and normal to increased raclopride binding with a rostrocaudal gradient similar to that found in idiopathic PD. This review emphasizes the importance of testing for SCA2 in patients with parkinsonism and a family history of neurodegenerative disorders. Testing for SCA2 is also important in studies of inherited parkinsonism.

Profile of families with Parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2)

The familial occurrence of Parkinson’s disease was noted as early as 1880, by Charcot’s student, Leroux.1 More recently, the discovery of several genetic causes and risk factors for parkinsonism has increased awareness of the importance of genetics in this and other complex neurological disorders. The phenotypic spectrum of pathogenic loci is wider than that of classic PD; it probably includes Lewy-body dementia, some forms of essential tremor, and other disorders. The discovery of causal mutations in the gene for_-synuclein2, parkin3, and the discovery of genetic linkages to chromosome (Ch) 2p4, 4p5, and Iq6, have revolutionized the field of Parkinson’s disease. Parkinsonism connotes a clinical syndrome including resting tremor, bradykinesia, rigidity, gait disturbance, and postural instability, along with other “secondary” features; the most common cause of parkinsonism is Parkinson’s Disease (PD)7. Supranuclear gaze palsy, prominent autonomic symptoms, early dementia, or hallucinosis suggest other disorders, which may have important biological overlaps with PD (including Progressive Supranuclear Palsy, multiple system atrophy, and diffuse Lewy body disease, for example). Clinical diagnosis, despite validated criteria8,9, remains accurate only ~80% percent of the time; pathological diagnosis remains the “goldstandard”10. Pathological hallmarks of PD include Lewy bodies, particularly in the substantia nigra pars compacta (SNpc)10,11. Of interest from a genetico-pathological standpoint, Lewy bodies stain with both a-synuclein and ubiquitin antibodies11.

Familial Variants of Parkinson’s Disease

Whole-genome association analyses have begun to yield confirmed findings for genetic risk variants for complex disease. As the first reports of its application to neurological disease are described, we review this progress, explain the principles of the analysis, and discuss what the future is likely to be in this exciting area. Arch Neurol. 2008;65(3):319-321 The human genome draft sequence released in 2001 1,2 was a consensus sequence based on the stitching together of DNAsequencesfromclonesderivedfrom many individuals; at best, this corresponded to an imperfect sketch of the human sequence and certainly represented no one person. The immediate utility of the human draft DNA sequence was that it provided a map to allow scientists to localize genes that were mutated in mendelian disease. It did not directly help us to understandthemoresubtledifferencesbetweenus,includingpredispositionstothe many common diseases that afflict humans. These common diseases, which include most cases of neurological disease such as most amyotrophic lateral sclerosis, Parkinson disease, Alzheimer disease,stroke,braintumors,manyothercan

Charting a Course for Genetic Discovery in Neurological Diseases

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TREM2 Variants in Alz hei mer's Disease

Profile of families with Parkinsonism-predominant spinocerebellar ataxia type 2 (SCA2)

Familial Variants of Parkinson’s Disease

Charting a Course for Genetic Discovery in Neurological Diseases