期刊
NEURON
卷 79, 期 5, 页码 873-886出版社
CELL PRESS
DOI: 10.1016/j.neuron.2013.06.046
关键词
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资金
- NINDS [P30 NS069375-01A1]
- Department of Veterans Affairs
- National Institutes of Health Institute on Aging [R01 AG030144, R01 AG18440, R01 AG10435]
- California Initiative for Regenerative Medicine Award
- Larry L. Hillblom Foundation
- John Douglas French Alzheimer's Foundation
- National Science Foundation predoctoral fellowship
- Kirschstein NRSA predoctoral fellowship
- National Institute of Neurological Disorders and Stroke (National Brain and Tissue Resource for Parkinson's Disease and Related Disorders) [U24 NS072026]
- National Institute on Aging (Arizona Alzheimer's Disease Core Center) [P30 AG19610]
- Arizona Department of Health Services (Arizona Alzheimer's Research Center) [211002]
- Arizona Biomedical Research Commission [4001, 0011, 05-901, 1001]
- Michael J. Fox Foundation for Parkinson's Research
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 in vitro 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.
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