Chronic TREM2 activation exacerbates A beta-associated tau seeding and spreading

Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene are associated with increased risk for late-onset AD. Genetic loss of or decreased TREM2 function impairs the microglial response to amyloid-beta (A beta) plaques, resulting in more diffuse A beta plaques and increased peri-plaque neuritic dystrophy and AD-tau seeding. Thus, microglia and TREM2 are at a critical intersection of A beta and tau pathologies in AD. Since genetically decreasing TREM2 function increases A beta-induced tau seeding, we hypothesized that chronically increasing TREM2 signaling would decrease amyloid-induced tau-seeding and spreading. Using a mouse model of amyloidosis in which AD-tau is injected into the brain to induce A beta-dependent tau seeding/spreading, we found that chronic administration of an activating TREM2 antibody increases peri-plaque microglial activation but surprisingly increases peri-plaque NP-tau pathology and neuritic dystrophy, without altering A beta plaque burden. Our data suggest that sustained microglial activation through TREM2 that does not result in strong amyloid removal may exacerbate A beta-induced tau pathology, which may have important clinical implications.

Automated summary

Variants in the TREM2 gene are associated with increased risk for late-onset AD, and decreased function of TREM2 can affect microglial response to Aβ plaques. Chronic increase of TREM2 signaling may exacerbate the Aβ-induced tau pathology.