title: Defects in cytokine-mediated neuroprotective glial responses to excitotoxic hippocampal injury in senescence-accelerated mouse.
abstract: Aging is a result of damage accumulation, and understanding of the mechanisms of aging requires exploration of the cellular and molecular systems functioning to control damage. Senescence-accelerated mouse prone 10 (SAMP10) has been established as an inbred strain exhibiting accelerated aging with an earlier onset of cognitive impairment due to neurodegeneration than the senescence-resistant control (SAMR1) strain. We hypothesized that tissue-protective responses of glial cells are impaired in SAMP10 mice. We injected kainic acid (KA) to induce hippocampal injury and studied how cytokines were upregulated on Day 3 using 3-month-old SAMP10 and SAMR1 mice. Following microarray-based screening for upregulated genes, we performed real-time RT-PCR and immunohistochemistry. Results indicated well-orchestrated cytokine-mediated glial interactions in the injured hippocampus of SAMR1 mice, in which microglia-derived interferon (IFN)-γ stimulated astrocytes via IFN-γ receptor and thereby induced expression of CXCL10 and macrophage inflammatory protein (MIP)-1α, and activated microglia produced granulocyte-macrophage colony-stimulating factor (GM-CSF) and osteopontin (OPN). OPN was the most strongly upregulated cytokine. CD44, an OPN receptor, was also strongly upregulated in the neuropil, especially on neurons and astrocytes. KA-induced hippocampal upregulation of these cytokines was strikingly reduced in SAMP10 mice compared to SAMR1 mice. On Day 30 after KA injection, SAMP10 but not SAMR1 mice exhibited hippocampal layer atrophy. Since the OPN-CD44 system is essential for neuroprotection and remodeling, these findings highlight the defects of SAMP10 mice in cytokine-mediated neuroprotective glia-neuron interactions, which may be associated with the mechanism underlying the vulnerability of SAMP10 mice to age-related neurodegeneration.
authors.affiliation: Department of Pathology, Institute for Developmental Research, Aichi Human Service Center, 713-8 Kamiya, Kasugai, Aichi 480-0392, Japan.
authors.forename: Sanae
authors.initials: S
authors.lastname: Hasegawa-Ishii
authors.forename: Shiro
authors.initials: S
authors.lastname: Takei
authors.forename: Muneo
authors.initials: M
authors.lastname: Inaba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Umegaki
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Chiba
authors.forename: Ayako
authors.initials: A
authors.lastname: Furukawa
authors.forename: Noriko
authors.initials: N
authors.lastname: Kawamura
authors.forename: Masanori
authors.initials: M
authors.lastname: Hosokawa
authors.forename: Atsuyoshi
authors.initials: A
authors.lastname: Shimada
mesh_terms: D000375:Aging / Q000235:genetics* / Q000502:physiology*; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D048429:Cell Size; D016207:Cytokines / Q000502:physiology*; D015870:Gene Expression / Q000187:drug effects; D006624:Hippocampus / Q000473:pathology*; D018960:Hyaluronan Receptors / Q000276:immunology; D007150:Immunohistochemistry; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D008818:Mice, Neurologic Mutants; D017628:Microglia / Q000276:immunology / Q000473:pathology; D009457:Neuroglia / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D015854:Up-Regulation / Q000235:genetics / Q000502:physiology
chemical_list: D016207:Cytokines; D018960:Hyaluronan Receptors; D009498:Neurotoxins; D007608:Kainic Acid