title: Blood-brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice.
abstract: Accumulating evidence indicates that obesity accelerates the onset of cognitive decline. While mechanisms are still being identified, obesity promotes peripheral inflammation and increases blood-brain barrier (BBB) permeability. However, no studies have manipulated vascular permeability in obesity to determine whether BBB breakdown underlies memory deficits. Protein kinase Cβ (PKCβ) activation destabilizes the BBB, and we used a PKCβ inhibitor (Enzastaurin) to block BBB leakiness in leptin receptor-deficient (db/db) mice. Enzastaurin reversed BBB breakdown in db/db mice and normalized hippocampal function without affecting obesity or metabolism. Flow cytometric analysis of forebrain mononuclear cells (FMCs) from db/db mice revealed macrophage infiltration and induction of the activation marker MHCII in microglia and macrophages. Enzastaurin eliminated macrophage infiltration and MHCII induction, and protein array profiling revealed parallel reductions in IL1β, IL6, MCP1, and TNFα. To investigate whether these signals attract peripheral monocytes, FMCs from Wt and db/db mice were plated below migration inserts containing peritoneal macrophages. Peritoneal macrophages from db/db mice exhibit increases in transmigration that were blocked by recombinant IL1RA. These studies indicate that BBB breakdown impairs cognition in obesity and diabetes by allowing macrophage infiltration, with a potential role for IL1β in trafficking of peripheral monocytes into the brain.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA astranahan@gru.edu.
authors.forename: Alexis M
authors.initials: AM
authors.lastname: Stranahan
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Shuai
authors.initials: S
authors.lastname: Hao
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Aditi
authors.initials: A
authors.lastname: Dey
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Yu
authors.affiliation: Department of Oral Biology, Medical College of Georgia, Georgia Regents University Augusta, GA, USA.|Plastic Surgery Section, Department of Surgery Medical College of Georgia, Georgia Regents University, Augusta, GA, USA.
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects / Q000378:metabolism*; D002199:Capillary Permeability; D002465:Cell Movement; D060825:Cognitive Dysfunction / Q000209:etiology*; D053583:Interleukin-1beta / Q000502:physiology; D008264:Macrophages / Q000166:cytology*; D008569:Memory Disorders / Q000209:etiology; D051379:Mice; D009000:Monocytes / Q000166:cytology; D009765:Obesity / Q000503:physiopathology; D054411:Receptors, Leptin / Q000172:deficiency*
chemical_list: D053583:Interleukin-1beta; D054411:Receptors, Leptin; C515447:leptin receptor, mouse
keywords: Diabetes; hippocampus; inflammation; learning and memory; microglia; obesity