| Literature DB >> 31257024 |
Bradlee L Heckmann1, Brett J W Teubner2, Bart Tummers1, Emilio Boada-Romero1, Lacie Harris1, Mao Yang1, Clifford S Guy1, Stanislav S Zakharenko2, Douglas R Green3.
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 β-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 β-amyloid. This inflammation and β-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 β-amyloid deposition.Entities:
Keywords: Alzheimer’s Disease; LC3-associated endocytosis; LC3-associated phagocytosis; autophagy; microglia; neurodegeneration; neuroinflammation; receptor-mediated endocytosis; tau pathology; β-amyloid
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Year: 2019 PMID： 31257024 PMCID： PMC6689199 DOI： 10.1016/j.cell.2019.05.056
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 66.850