ABSTRACT
Cognitive decline remains an unaddressed problem for the elderly. We show that myelination is highly active in young mice and greatly inhibited in aged mice, coinciding with spatial memory deficits. Inhibiting myelination by deletion of Olig2 in oligodendrocyte precursor cells impairs spatial memory in young mice, while enhancing myelination by deleting the muscarinic acetylcholine receptor 1 in oligodendrocyte precursor cells, or promoting oligodendroglial differentiation and myelination via clemastine treatment, rescues spatial memory decline during aging.
Subject(s)
Aging/pathology , Demyelinating Diseases/pathology , Memory Disorders/pathology , Myelin Sheath/pathology , Aging/genetics , Animals , Demyelinating Diseases/complications , Demyelinating Diseases/genetics , Demyelinating Diseases/metabolism , Memory Disorders/etiology , Memory Disorders/genetics , Memory Disorders/metabolism , Mice , Mice, Transgenic , Myelin Basic Protein/genetics , Myelin Basic Protein/metabolism , Myelin Sheath/metabolism , Oligodendrocyte Precursor Cells/metabolism , Oligodendrocyte Precursor Cells/pathology , Oligodendrocyte Transcription Factor 2/genetics , Oligodendrocyte Transcription Factor 2/metabolism , Oligodendroglia/metabolism , Oligodendroglia/pathologyABSTRACT
This study aimed at investigating the response of lens epithelial cells in postnatal mice to Imatinib (Glivec®, a potent inhibitor of platelet-derived growth factor receptor (PDGFR)) treatment. Mouse eyes were sampled 10 days after administration of Imatinib (0.5 mg·g(-1)·day(-1)) for 3 days, at either 7, 14, or 21 days postpartum. Structural changes of lens were revealed by routine H.E. staining. Levels of proliferation and apoptosis were revealed by BrdU incorporation and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, respectively, and immunofluorescent staining with anti-PDGFRα antibody was carried out on the sections of eyeball. PDGFRα and p-PDGFRαprotein levels were evaluated by Western blot. Our results indicated that administration of Imatinib led to blockade of PDGFR signaling. Formation of cataracts was found only in those mice where treatment started from 7 days postpartum (P7), but was not observed in those samples from P14 nor P21. Fiber cells were disorganized in cataract lens core as observed histologically, and migration of epithelial cells was also inhibited. No apoptosis was detected with the TUNEL method. Our results indicated blockade of PDGFR at the neonatal stage (P7) would lead to cataracts and lens fiber cells disorganization, suggesting that PDGFR signaling plays a time-specific and crucial role in the postnatal development of lens in the mouse, and also may provide a new approach to produce a congenital cataract animal model.
Subject(s)
Cataract/chemically induced , Epithelial Cells/drug effects , Lens, Crystalline/drug effects , Piperazines/toxicity , Protein Kinase Inhibitors/toxicity , Pyrimidines/toxicity , Receptor, Platelet-Derived Growth Factor alpha/antagonists & inhibitors , Animals , Animals, Newborn , Apoptosis/drug effects , Benzamides , Cataract/metabolism , Cataract/pathology , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Epithelial Cells/metabolism , Epithelial Cells/pathology , Imatinib Mesylate , In Situ Nick-End Labeling , Lens, Crystalline/metabolism , Lens, Crystalline/pathology , Mice , Mice, Inbred BALB C , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Signal Transduction/drug effects , Time FactorsABSTRACT
This study aimed at evaluating whether apoptosis of interstitial cells of Cajal (ICC), smooth muscle cells (SMC), and enteric neurons was involved in a guinea pig model of intestinal ischemia and reperfusion injury. The small intestinal segments were resected at either 6 (I60/R6h) and 12 h (I60/R12h) or 7 (I60/R7d) to 14 (I60/R14d) days after 60 min intestinal ischemia in the adult guinea pigs and studied by immunohistochemistry with anti-Kit, 5-bromo-2'-deoxyuridine (BrdU), alpha-smooth muscle actin, vimentin, and beta-tublin III antibodies. Also, apoptosis was tested by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method. In the I60/R12h injury, there was a approximately 50% decrease of Kit+ cells in cell numbers at the level of myenteric plexus and a number of Kit-/vimentin-positive cells were labeled by TUNEL. Also, a few SMC and enteric neurons were TUNEL positive. The Kit+ ICC recovered to normal and a number of Kit-/BrdU-double-positive cells were observed in the I60/R14d group. Our results indicated that the intestinal I/R injury could lead to apoptosis of ICC, SMC, and enteric neurons which may contribute to the gastrointestinal motility disorders, and proliferation was involved in the recovery of ICC.
