LC3-Associated Endocytosis Facilitates β-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer's Disease
Authors: Emilio Boada-Romero
Douglas R Green
Brett J W Teubner
Bradlee L Heckmann
Lacie Harris
Mao Yang
Stanislav S Zakharenko
Clifford S Guy
Bart Tummers
Journal: Cell (2019)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Alzheimer’s Disease; LC3-associated endocytosis; LC3-associated phagocytosis; autophagy; microglia
Affiliations: Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA., Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address: .

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. 

Retracted: No

PubPeer comments:
 There appears to be a panel duplication in one of the supplementary figures. The flow cytometry data for the two different genotypes looks identical. Duplicated plots are boxed in red. https: i.imgur.com YqKfGmY.jpg , 
 There seems to be some mislabeling of IHC images in this paper. In figure 4A the section shown for the FIP200 +Cre is the same section that is shown in figure 5A as the FIP200 -Cre. I ve circled some features that identify the section. The most obvious one is the bubble in the lower right hand corner of the image. https: imgur.com 0BsgT1T https: i.imgur.com 0BsgT1T.jpg Also the same section appears in figure 6A. This means that the authors acquired 4 channels of fluorescence from a single image (3 antibodies + DAPI). The are no details for this triple IF staining protocol provided in the methods section (secondary antibodies etc). It would be useful to have this information. Also I am unable to locate the phospho-Tau antibody listed in the STAR methods. The RRID# doesn t listed match anything on the Thermo Fisher website. https: imgur.com N77DIHX https: i.imgur.com N77DIHX.jpg , 
 December 10, 2020  Our paper focused on the identification of LC3-associated endocytosis and the role of this pathway in the clearance of beta-amyloid and mitigation of neurodegeneration in Alzheimeru2019s Disease. Following publication, we have identified two errors in the original version of the article. First, the same FACS plot for TMEM119 expression was inadvertently presented for both 5xFAD Rubicon + u2212 and 5xFAD Rubicon u2212 u2212 as shown in Figure S5C. A revised version of the figure is shown below with the correct TMEM119 FACS plot for the 5xFAD Rubicon + u2212, the original plot for the 5xFAD Rubicon u2212 u2212 was correct and is therefore unchanged. The second inadvertent error was the misplacement mislabeling of the representative images for hippocampal Iba1 staining in FIP200fl flMG-cre+ compared to FIP200fl flMG-creu2212 mice found in Figure 4A. The original labels are reversed and therefore have been corrected in the revised version of Figure 4 below. These errors occurred during the preparation of the figures and do not affect the results in the paper or the interpretation of the data. The figures have been corrected online. We apologize for any confusion these errors may have caused. ![file] ![file] ,