title: P2Y4 receptor-mediated pinocytosis contributes to amyloid beta-induced self-uptake by microglia.
abstract: Brain disturbances, like injuries or aberrant protein deposits, evoke nucleotide release or leakage from cells, leading to microglial chemotaxis and ingestion. Recent studies have identified P2Y12 purinergic receptors as triggers for microglial chemotaxis and P2Y6 receptors as mediators for phagocytosis. However, pinocytosis, known as the internalization of fluid-phase materials, has received much less attention. We found that ATP efficiently triggered pinocytosis in microglia. Pharmacological analysis and knockdown experiments demonstrated the involvement of P2Y4 receptors and the phosphatidylinositol 3-kinase/Akt cascade in the nucleotide-induced pinocytosis. Further evidence indicated that soluble amyloid beta peptide 1-42 induced self-uptake in microglia through pinocytosis, a process involving activation of P2Y4 receptors by autocrine ATP signaling. Our results demonstrate a previously unknown function of ATP as a "drink me" signal for microglia and P2Y4 receptors as a potential therapeutic target for the treatment of Alzheimer's disease.
authors.affiliation: Institute of Neuroscience and Key Laboratory of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Hui-quan
authors.initials: HQ
authors.lastname: Li
authors.forename: Cong
authors.initials: C
authors.lastname: Chen
authors.forename: Ying
authors.initials: Y
authors.lastname: Dou
authors.forename: Hang-jun
authors.initials: HJ
authors.lastname: Wu
authors.forename: Yi-jun
authors.initials: YJ
authors.lastname: Liu
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Lou
authors.forename: Jian-min
authors.initials: JM
authors.lastname: Zhang
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Li
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Shumin
authors.initials: S
authors.lastname: Duan
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D019898:Autocrine Communication; D002478:Cells, Cultured; D005260:Female; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D017628:Microglia / Q000502:physiology*; D010446:Peptide Fragments / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010873:Pinocytosis; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058910:Purinergic P2 Receptor Agonists / Q000494:pharmacology; D051381:Rats; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D015398:Signal Transduction; D059010:Single-Cell Analysis; D059008:Time-Lapse Imaging
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D058910:Purinergic P2 Receptor Agonists; D018048:Receptors, Purinergic P2; C075222:amyloid beta-protein (1-42); C104749:purinoceptor P2Y4; C022571:adenosine 5'-O-(3-thiotriphosphate); D000255:Adenosine Triphosphate; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt