title: Toll-interacting protein deficiency promotes neurodegeneration via impeding autophagy completion in high-fat diet-fed ApoE-/-mouse model.
abstract: The excessive accumulation of specific cellular proteins or autophagic vacuoles (AVs) within neurons is a pathologic hallmark of neurodegenerative diseases. Constitutive autophagy in neurons prevents abnormal intracellular protein aggregation and is critical for maintaining cell survival. Since our previous study showed that Toll-interacting protein (Tollip)-deficient macrophages had constitutive disruption of endosome-lysosome fusion, we hypothesize that Tollip deficiency may also promote neuron death via blockage of autophagy completion. Indeed, we observed significantly higher levels of neuron death in the brain regions of cerebral cortex, hippocampus, and cerebellum from ApoE-/-/Tollip-/-mice as compared to ApoE-/-mice fed with high fat diet (HFD). We further documented diminished density of neurons and increased ratios of TUNEL positive cells in the hippocampus of ApoE-/-/Tollip-/-mice. The ultrastructural electron microscopy analyses revealed neuron cell shrinkage as well as loss of intracellular structure in brain tissues from ApoE-/-/Tollip-/-mice. There was dramatic accumulation of autophagosomes in the cytoplasm, elevated accumulation of β-amyloid and α-synuclein, and increased levels of p62 and Parkin in the brain tissues from ApoE-/-/Tollip-/-mice as compared to ApoE-/-mice. Our data suggest that Tollip may play a crucial role in sustaining neuron health by facilitating the completion of autophagy, and that Tollip-deficiency may accelerate neuron death related to neurological disease such as Alzheimer's disease.
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Keqiang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.|Department of Biomedical Sciences & Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Ruoxi
authors.initials: R
authors.lastname: Yuan
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Geng
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Taojing
authors.initials: T
authors.lastname: Ran
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Kowalski
authors.affiliation: College of Life Sciences, Hebei Normal University, Shijiazhuang, 050024, China.
authors.forename: Jingze
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Biological Sciences, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.|Department of Biomedical Sciences & Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA 24061, USA.
authors.forename: Liwu
authors.initials: L
authors.lastname: Li
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D001343:Autophagy / Q000235:genetics*; D001921:Brain / Q000166:cytology; D056547:CA1 Region, Hippocampal / Q000473:pathology; D048429:Cell Size; D059305:Diet, High-Fat; D011992:Endosomes / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency* / Q000235:genetics*; D008247:Lysosomes / Q000502:physiology; D008264:Macrophages / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D046529:Microscopy, Electron, Transmission; D009410:Nerve Degeneration / Q000235:genetics*; D010588:Phagosomes / Q000502:physiology; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D001057:Apolipoproteins E; D047908:Intracellular Signaling Peptides and Proteins; C497605:Snca protein, mouse; C485837:Tollip protein, mouse; D051844:alpha-Synuclein
keywords: Autophagy; Cell death; Neurodegenerative disease; Tollip