title: Cathepsin D deficiency induces oxidative damage in brain pericytes and impairs the blood-brain barrier.
abstract: Recent evidence suggests that peripheral blood mononuclear cells (PBMCs) contribute to the pathogenesis of neuropathological changes in patients with neuronal ceroid lipofuscinosis (NCL) and lysosomal storage diseases. In order to examine the possible increase in the permeability of the blood-brain-barrier (BBB) and resultant infiltration of PBMCs due to cathepsin D (CatD) deficiency, a process underlying the onset of congenital NCL, we examined structural changes in brain vessels in CatD-/- mice. Consequently, the mean diameter of the brain vessels in the cerebral cortex on postnatal day 24 (P24) was significantly larger in CatD-/- mice than in wild-type mice. Furthermore, the mean number of brain pericytes in CatD-/- mice began to decline significantly on P16 and almost disappeared on P24, and oxidative DNA damage was first detected in brain pericytes on P12. Examinations with electron microscopy revealed that brain pericytes were laden with dense granular bodies, cytoplasmic vacuoles and lipid droplets. The infiltration of PBMCs characterized by segmented nucleus laden with dense granular bodies was also noted in the cerebral cortex of CatD-/- mice. When primary cultured microglia prepared from enhanced green fluorescent protein (GFP)-expressing transgenic rats were injected into the common carotid artery, GFP-positive microglia were detected in the brain parenchyma of CatD-/-, but not wild-type, mice. Moreover, pepstatin A, a specific aspartic protease inhibitor, induced mitochondria-derived reactive oxygen species (ROS) production in the isolated brain pericytes, which decreased the cell viability. These observations suggest that increased lysosomal storage due to CatD deficiency causes oxidative damage in brain pericytes, subsequently resulting in an increased vessel diameter, enhanced permeability of the BBB and the infiltration of PBMCs. Therefore, protecting brain pericytes against lysosomal storage-induced oxidative stress may represent an alternative treatment strategy for congenital NCL.
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Okada
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Institution of Geriatric Qinghai Provincial Hospital, Shining, 810007, China.
authors.forename: Aiqin
authors.initials: A
authors.lastname: Zhu
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Junjun
authors.initials: J
authors.lastname: Ni
authors.affiliation: Division of Oral Biological Sciences, Department of Molecular Cell Biology & Oral Anatomy, Faculty of Dental Science, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Jingqi
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Endodontology and Operative Dentistry, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yoshito
authors.initials: Y
authors.lastname: Yoshimine
authors.affiliation: Instutute für Molekuläre Medizin und Zellforschung, Albert-Ludwigs-Universität, Freiburg D-79104, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Peters
authors.affiliation: Department of Biochemistry, University of Kiel, D-24098 Kiel, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Department of Aging Science and Pharmacology, Faculty of Dental Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: nakan@dent.kyushu-u.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakanishi
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000378:metabolism*; D002199:Capillary Permeability; D002402:Cathepsin D / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002540:Cerebral Cortex / Q000166:cytology / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018384:Oxidative Stress; D020286:Pericytes / Q000378:metabolism* / Q000648:ultrastructure
chemical_list: D002402:Cathepsin D
keywords: Brain pericyte; Cathepsin D; Lysosomal storage; Microglia; Reactive oxygen species