LC3-Associated Endocytosis Facilitates ?-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease.

ABSTRACT: The expression of some proteins in the autophagy pathway declines with age, which may impact neurodegeneration in diseases, including Alzheimer's Disease. We have identified a novel non-canonical function of several autophagy proteins in the conjugation of LC3 to Rab5⁺, clathrin⁺ endosomes containing ?-amyloid in a process of LC3-associated endocytosis (LANDO). We found that LANDO in microglia is a critical regulator of immune-mediated aggregate removal and microglial activation in a murine model of AD. Mice lacking LANDO but not canonical autophagy in the myeloid compartment or specifically in microglia have a robust increase in pro-inflammatory cytokine production in the hippocampus and increased levels of neurotoxic ?-amyloid. This inflammation and ?-amyloid deposition were associated with reactive microgliosis and tau hyperphosphorylation. LANDO-deficient AD mice displayed accelerated neurodegeneration, impaired neuronal signaling, and memory deficits. Our data support a protective role for LANDO in microglia in neurodegenerative pathologies resulting from ?-amyloid deposition.

SUBMITTER: Heckmann BL 

PROVIDER: S-EPMC6689199 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature