Disease Progression-Dependent Effects of TREM2 Deficiency in a Mouse Model of Alzheimer's Disease

Abstract

Neuroinflammation is an important contributor to Alzheimer's disease (AD) pathogenesis, as underscored by the recent identification of immune-related genetic risk factors for AD, including coding variants in the gene TREM2 (triggering receptor expressed on myeloid cells 2). Understanding TREM2 function promises to provide important insights into how neuroinflammation contributes to AD pathology. However, studies so far have produced seemingly conflicting results, with reports that amyloid pathology can be both decreased and increased in TREM2-deficient AD mouse models. In this study, we unify these previous findings by demonstrating that TREM2 deficiency ameliorates amyloid pathology early, but exacerbates it late in disease progression in the APPPS1-21 mouse model of AD. We also demonstrate that TREM2 deficiency decreases plaque-associated myeloid cell accumulation by reducing cell proliferation, specifically late in pathology. In addition, TREM2 deficiency reduces myeloid cell internalization of amyloid throughout pathology, but decreases inflammation-related gene transcript levels selectively late in disease progression. Together, these results suggest that TREM2 plays distinct functional roles at different stages in AD pathology.

Alzheimer's disease pathology in Nasu-Hakola disease brains

“…Plaque accumulation is exacerbated at later ages in a TREM2 knockout AD mouse model (17). In AD patients, Aβ plaques appear a decade or two before clinical symptoms of AD (18).…”

Microglia in Alzheimer’s disease

“…A recent report indicated that the opposing results from previous work might reflect a disease progression-dependent influence of TREM2 deficiency on AD pathology. While TREM2 deficiency in young APP/PS1-21 mice ameliorated amyloid pathology, it enhanced amyloid deposition at later disease stages (157). Additionally, TREM2 deficiency in aged mice decreased plaque-associated myeloid cell accumulation by reducing proliferation (157).…”

“…While TREM2 deficiency in young APP/PS1-21 mice ameliorated amyloid pathology, it enhanced amyloid deposition at later disease stages (157). Additionally, TREM2 deficiency in aged mice decreased plaque-associated myeloid cell accumulation by reducing proliferation (157). Considering the dual role of TREM2, a longitudinal assessment of TREM2 in conditional knockout models will reveal important effects of TREM2 signaling on myeloid cells during AD progression to support development of TREM2-directed therapeutics for different disease stages.…”

TREM2, Microglia, and Neurodegenerative Diseases

“…A major difference between these two studies, other than the animal models, was the age at which the animals were analyzed -8.5 months in the [ 5 3 0 _ T D $ D I F F ] 5ÂFAD and 4 months in the APPPS1 experiments. A recent study attempted to reconcile these results by looking at the cortex of APPPS1 mice at different ages, reporting that plaque pathology was decreased at 2 months of age, but increased at 8 months of age, in Trem2-deficient mice [142]. This may imply that the effects of TREM2 activity at early or late stages of disease could be detrimental or beneficial, respectively.…”