Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer's disease

Abstract

Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk for Alzheimer’s disease. TREM2 mutations are the genetic basis for a condition characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (p.Trp198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls we report replication of the AD risk association at rs75932628 within TREM2. These data suggest that mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general and that potentially this class of TREM2 variant carriers with dementia should be considered a molecularly distinct form of neurodegenerative disease.

Apolipoprotein E Is a Ligand for Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)

“…Recently, the missense TREM2-R47H mutation has been identified and validated as a risk variant for LOAD (6,7,11,(15)(16)(17)(18)(19). Although numerous studies have investigated the genetic link between TREM2 variants and neurodegenerative diseases, only two other studies have empirically tested the functional outcome of disease-associated mutations (23,51).…”

[P4–449]: The Alzheimer's Disease‐associated R47h Variant of Trem2 Has an Altered Glycosylation Pattern and Protein Stability

“…TREM2 mutations are associated with neurological disorders (Bird, 2013;Giraldo et al, 2013;Guerreiro et al, 2013;Luis et al, 2014), although it is not well known how TREM2 contributes to these diseases. We found in our current analyses that the AD-associated R47H variant of TREM2 has increased terminal glycosylation with complex oligosaccharides in the Golgi apparatus and decreased solubility.…”

Triggering receptor expressed on myeloid cells-2 is involved in prion-induced microglial activation but does not contribute to prion pathogenesis in mouse brains

“…The finding that TREM2 variants act as strong genetic risk factors for Alzheimer's disease and many other neurodegenerative diseases (Benitez, et al, 2013,Borroni, et al, 2014,Cady, et al, 2014,Giraldo, et al, 2013,Gonzalez Murcia, et al, 2013,R. Guerreiro, et al, 2013a,R.…”

“…These findings have spurred numerous studies addressing the association between TREM2 and AD and other neurodegenerative diseases. Although negatives have been reported (Jiao, et al, 2014,Miyashita, et al, 2014,Ruiz, et al, 2014,Yu, et al, 2014, the association between TREM2 variants and AD has been confirmed by most studies (Benitez, et al, 2013,Giraldo, et al, 2013,Gonzalez Murcia, et al, 2013,Luis, et al, 2014,Slattery, et al, 2014. Moreover, TREM2 variants were also found to be associated with frontotemporal dementia-like syndrome or FTD (Borroni, et al, 2014,R.…”