title: Thrombospondin-1 prevents amyloid beta-mediated synaptic pathology in Alzheimer's disease.
abstract: Alzheimer's disease (AD) is characterized by impaired cognitive function and memory loss, which are often the result of synaptic pathology. Thrombospondin (TSP) is an astrocyte-secreted protein, well known for its function as a modulator of synaptogenesis and neurogenesis. Here, we investigated the effects of TSP-1 on AD pathogenesis. We found that the level of TSP-1 expression was decreased in AD brains. When we treated astrocytes with amyloid beta (Aβ), secreted TSP-1 was decreased in autophagy-dependent manner. In addition, treatment with Aβ induced synaptic pathology, such as decreased dendritic spine density and reduced synaptic activity. These effects were prevented by coincubation of TSP-1 with Aβ, which acts through the TSP-1 receptor alpha-2-delta-1 in neurons. Finally, intrasubicular injection with TSP-1 into AD model mouse brains mitigated the Aβ-mediated reduction of synaptic proteins and related signaling pathways. These results indicate that TSP-1 is a potential therapeutic target in AD pathogenesis.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sung Min
authors.initials: SM
authors.lastname: Son
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Dong Woo
authors.initials: DW
authors.lastname: Nam
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Moon-Yong
authors.initials: MY
authors.lastname: Cha
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Kyung Ho
authors.initials: KH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jayoung
authors.initials: J
authors.lastname: Byun
authors.affiliation: Center for Neuromedicine, Brain Science Institute, KIST, Seoul, Korea; Department of Neurology, Boston University, Boston, MA, USA.
authors.forename: Hoon
authors.initials: H
authors.lastname: Ryu
authors.affiliation: Department of Biochemistry and Biomedical Sciences, Seoul National University College of Medicine, Seoul, Korea. Electronic address: inhee@snu.ac.kr.
authors.forename: Inhee
authors.initials: I
authors.lastname: Mook-Jung
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000009:adverse effects*; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001343:Autophagy; D001921:Brain / Q000378:metabolism; D004195:Disease Models, Animal; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction; D013569:Synapses / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D019700:Thrombospondin 1 / Q000378:metabolism / Q000502:physiology* / Q000627:therapeutic use*
chemical_list: D016229:Amyloid beta-Peptides; D019700:Thrombospondin 1
keywords: Alzheimer's disease (AD); Aβ; Neuron-astrocyte crosstalk; Synaptic dysfunction; TSP-1