In CD33 modulates TREM2: convergence of Alzheimer loci, Chan et al. investigated the connections between various genetic variants associated with risk of late-onset Alzheimer’s Disease (AD). They worked in monocytes, a type of white blood cell that can differentiate further into more targeted immune cells, and based their investigation on large-scale studies associating genetic mutations with disease susceptibility. They started by validating their model system: they confirmed that the genes they focused on were predominantly expressed in monocytes and that AD-associated alleles were correlated with the expected protein-level changes. In the TREM1/2 receptor locus, in which the former is pro-inflammatory and the latter anti-inflammatory, they found that the association of TREM1 mutations with AD results from changes in signaling balance rather than a simple reduction of TREM1, suggesting a potential effect of TREM2. In the CD33 locus, they found that two mutations that increase expression have opposite effects on AD susceptibility, leaving the connection between CD33 expression and AD murky. Interestingly, they found an effect of CD33 on TREM2 expression, suggesting a potential connection between their associations with AD; their model suggested a link between CD33 suppression and decreased expression of TREM2. They hypothesized that the association between TREM2 and AD may have to do with accumulated amyloid damage over time. They concluded that the signaling connection between CD33 and TREM2 (and the similar connection between NME8 and PTK2B) could prove important for future studies improving understanding of the genetic and immune basis of AD.
By: Zach Altshuler