@article{18f81c4edbf542e9a5cecbdc5856b950,
title = "Microglial Beclin 1 Regulates Retromer Trafficking and Phagocytosis and Is Impaired in Alzheimer's Disease",
abstract = "Phagocytosis controls CNS homeostasis by facilitating the removal of unwanted cellular debris. Accordingly, impairments in different receptors or proteins involved in phagocytosis result in enhanced inflammation and neurodegeneration. While various studies have identified extrinsic factors that modulate phagocytosis in health and disease, key intracellular regulators are less understood. Here we show that the autophagy protein beclin 1 is required for efficient phagocytosis invitro and in mouse brains. Furthermore, we show that beclin 1-mediated impairments in phagocytosis are associated with dysfunctional recruitment of retromer to phagosomal membranes, reduced retromer levels, and impaired recycling of phagocytic receptors CD36 and Trem2. Interestingly, microglia isolated from human Alzheimer@s disease (AD) brains show significantly reduced beclin 1 and retromer protein levels. These findings position beclin 1 as a link between autophagy, retromer trafficking, and receptor-mediated phagocytosis and provide insight into mechanisms by which phagocytosis is regulated and how it may become impaired in AD",
author = "Lucin, {Kurt M.} and O'Brien, {Caitlin E.} and Gregor Bieri and Eva Czirr and Mosher, {Kira I.} and Abbey, {Rachelle J.} and Mastroeni, {Diego F.} and Joseph Rogers and Brian Spencer and Eliezer Masliah and Tony Wyss-Coray",
note = "Funding Information: The authors thank Dr. Saul Villeda and Dr. Joseph Castellano for critical review of the manuscript, Zhaoqing Ding for assistance with flow cytometry, Dr. Manuel Buttini for assistance with the ex vivo phagocytosis assay, Dr. Sergio Grinstein for providing the 2xFYVE-mRFP construct, the Stanford Virus Core (supported by NINDS P30 NS069375-01A1) for producing the lentiviruses used in this study, and Dr. Philipp Jaeger and Dr. Scott Small for helpful discussions of the manuscript. Funding for these studies was provided by the Department of Veterans Affairs (T.W.-C.), the National Institutes of Health Institute on Aging (R01 AG030144, T.W.-C. R01 AG18440, E.M.; R01 AG10435, E.M.), a California Initiative for Regenerative Medicine Award (T.W.-C.), The Larry L. Hillblom Foundation (K.M.L., T.W.-C.), The John Douglas French Alzheimer{\textquoteright}s Foundation (K.M.L.), a National Science Foundation predoctoral fellowship (K.I.M.), and a Kirschstein NRSA predoctoral fellowship (1 F31 AG040877-01A1, K.I.M.). We are also grateful to the Banner Sun Health Research Institute Brain and Body Donation Program of Sun City, AZ for the provision of human microglia. The Brain and Body Donation Program is supported by the National Institute of Neurological Disorders and Stroke (U24 NS072026 National Brain and Tissue Resource for Parkinson{\textquoteright}s Disease and Related Disorders), the National Institute on Aging (P30 AG19610 Arizona Alzheimer{\textquoteright}s Disease Core Center), the Arizona Department of Health Services (contract 211002, Arizona Alzheimer{\textquoteright}s Research Center), the Arizona Biomedical Research Commission (contracts 4001, 0011, 05-901 and 1001 to the Arizona Parkinson{\textquoteright}s Disease Consortium) and the Michael J. Fox Foundation for Parkinson{\textquoteright}s Research. ",
year = "2013",
month = sep,
day = "4",
doi = "10.1016/j.neuron.2013.06.046",
language = "English (US)",
volume = "79",
pages = "873--886",
journal = "Neuron",
issn = "0896-6273",
publisher = "Cell Press",
number = "5",
}