Blood-brain barrier breakdown promotes macrophage infiltration and cognitive impairment in leptin receptor-deficient mice

Alexis M. Stranahan, Shuai Hao, Aditi Dey, Xiaolin Yu, Babak Baban

Research output: Contribution to journalArticle

51 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2108-2121
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Volume36
Issue number12
DOIs
StatePublished - Dec 1 2016

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Keywords

  • Diabetes
  • hippocampus
  • inflammation
  • learning and memory
  • microglia
  • obesity

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine

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