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

Cell. 2019 Jul 25;178(3):536-551.e14. doi: 10.1016/j.cell.2019.05.056. Epub 2019 Jun 27.

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.

Keywords: Alzheimer’s Disease; LC3-associated endocytosis; LC3-associated phagocytosis; autophagy; microglia; neurodegeneration; neuroinflammation; receptor-mediated endocytosis; tau pathology; β-amyloid.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Autophagy-Related Protein 5 / deficiency
  • Autophagy-Related Protein 5 / genetics
  • Autophagy-Related Proteins / deficiency
  • Autophagy-Related Proteins / genetics
  • CD36 Antigens / metabolism
  • Cytokines / metabolism
  • Disease Models, Animal
  • Endocytosis*
  • Hippocampus / metabolism
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Transgenic
  • Microglia / cytology
  • Microglia / metabolism
  • Microtubule-Associated Proteins / metabolism*
  • RAW 264.7 Cells
  • Receptors, Immunologic / metabolism
  • Toll-Like Receptor 4 / metabolism

Substances

  • Amyloid beta-Peptides
  • Autophagy-Related Protein 5
  • Autophagy-Related Proteins
  • CD36 Antigens
  • Cytokines
  • Intracellular Signaling Peptides and Proteins
  • Map1lc3b protein, mouse
  • Membrane Glycoproteins
  • Microtubule-Associated Proteins
  • Rb1cc1 protein, mouse
  • Receptors, Immunologic
  • Toll-Like Receptor 4
  • Trem2 protein, mouse
  • rubicon protein, mouse