Chronic TREM2 activation exacerbates Aß-associated tau seeding and spreading.
J Exp Med
; 220(1)2023 01 02.
Article
em En
| MEDLINE
| ID: mdl-36219197
ABSTRACT
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-ß (Aß) plaques, resulting in more diffuse Aß plaques and increased peri-plaque neuritic dystrophy and AD-tau seeding. Thus, microglia and TREM2 are at a critical intersection of Aß and tau pathologies in AD. Since genetically decreasing TREM2 function increases Aß-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 Aß-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 Aß plaque burden. Our data suggest that sustained microglial activation through TREM2 that does not result in strong amyloid removal may exacerbate Aß-induced tau pathology, which may have important clinical implications.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Alzheimer
/
Amiloidose
Limite:
Animals
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article