Journal
CELL
Volume 178, Issue 3, Pages 536-+Publisher
CELL PRESS
DOI: 10.1016/j.cell.2019.05.056
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Funding
- US National Institutes of Health [AI40646, CA231620, AI138492, CA231423]
- Lupus Research Alliance
- ALSAC
- John H. Sununu Endowed Fellowship
- Paul Barrett Endowed Fellowship
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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 beta-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 b-amyloid. This inflammation and b-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 b-amyloid deposition.
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