Editors' ChoiceAlzheimer’s Disease

Taking TREM to the brain

Science Translational Medicine  11 Mar 2015:
Vol. 7, Issue 278, pp. 278ec41
DOI: 10.1126/scitranslmed.aaa9865

Alzheimer’s disease (AD) is a destructive disease characterized by accumulation of β-amyloid peptides into aggregates called plaques in the brain. Plaque removal by myeloid cells of the immune system, including microglia and macrophages, improves symptoms of AD in mouse models. However, dysregulated inflammation in the brain seems to be a key player in the pathogenesis of AD. Macrophages have been implicated in the development of neurodegenerative diseases through their production of proinflammatory mediators. However, the role of macrophages and the mechanisms involved in amyloid plaque clearance during AD are poorly understood.

In a new study, Jay et al. have investigated the role of a receptor called triggering receptor expressed on myeloid cells 2 (TREM2) in the pathogenesis of AD. TREM2 is known to promote microbial ingestion by macrophages and inhibits the secretion of proinflammatory mediators during pathogen recognition receptor engagement. Furthermore, TREM2 signaling favors the transcription of many anti-inflammatory cytokines. The authors sought to identify disease-relevant cell types that express TREM2 and examine the effects of loss of TREM2 function on AD pathologies. Initially, the authors identified TREM2-expressing cells around Congo red–positive amyloid plaques (Congo-red stain is used to diagnose amyloidosis) in two murine models of AD, and they observed similar expression patterns in two neuropathologically confirmed cases of human AD. Next, the authors showed that TREM2 protein colocalizes with plaque-associated Iba1+ cells (a myeloid cell marker) but not with markers of other brain cells that were not associated with plaques. Interestingly, flow cytometry analysis revealed that TREM2+ plaque–associated myeloid cells expressed markers characteristic of monocyte-derived macrophages. To determine the role of TREM2 in AD-like pathology, a mouse strain that naturally develops AD (called the APP/PS1 mouse) was crossed with mice lacking Trem2 (Trem2-/- mice). APP/PS1_Trem2+/+ mice exhibited robust accumulation of Iba1+ myeloid cells around plaques, whereas APP/PS1_Trem2-/- mice had a fivefold decrease in plaque-associated Iba1+ cells. Other cardinal features of APP/PS1_Trem2-/- mice included decreased expression of inflammatory cytokines, reduced amyloid-beta precursor protein expression in different brain regions, and reduced insoluble β-amyloid peptides, all suggesting a protective effect in AD.

Overall, this study provides important clues regarding the pathogenesis of AD and indicates that TREM2 inhibition could improve AD pathogenesis through several mechanisms: impaired transmigration of TREM2-negative cells across the blood-brain barrier, direct alteration of the brain vasculature to change cell trafficking, reduced chemotaxis of TREM2-deficient cells to amyloid plaques in the brain parenchyma, or shortened survival of these cells within the central nervous system. Although the authors did not identify the signals downstream of TREM2 activation, these findings open up new potential avenues for treating AD.

T. R. Jay et al., TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. jem.20142322 (2015). [Full Text]

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