Authors: Bradlee L. Heckmann, Brett J.W. Teubner, Bart Tummers, Emilio Boada-Romero, Lacie Harris, Mao Yang, Clifford S. Guy, Stanislav S. Zakharenko, Douglas R. Green
Summary: The expression of some proteins in the autophagy pathway declines with age, whichmay impact neurodegeneration in diseases, including Alzheimer’s Disease. We have identifieda novel non-canonical function of several autophagy proteins in the conjugation ofLC3 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 aggregateremoval and microglial activation in a murine model of AD. Mice lacking LANDO butnot canonical autophagy in the myeloid compartment or specifically in microglia havea robust increase in pro-inflammatory cytokine production in the hippocampus and increasedlevels of neurotoxic β-amyloid. This inflammation and β-amyloid deposition were associatedwith reactive microgliosis and tau hyperphosphorylation. LANDO-deficient AD mice displayedaccelerated neurodegeneration, impaired neuronal signaling, and memory deficits. Ourdata support a protective role for LANDO in microglia in neurodegenerative pathologiesresulting from β-amyloid deposition.
Source: Cell, 2019