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Hyperglycemia-Driven Neuroinflammation Compromises BBB Leading to Memory Loss in Both Diabetes Mellitus (DM) Type 1 and Type 2 Mouse Models

  • Slava Rom
  • Viviana Zuluaga-Ramirez
  • Sachin Gajghate
  • Alecia Seliga
  • Malika Winfield
  • Nathan A. Heldt
  • Mikhail A. Kolpakov
  • Yulia V. Bashkirova
  • Abdel Karim Sabri
  • Yuri Persidsky
Article

Abstract

End organ injury in diabetes mellitus (DM) is driven by microvascular compromise (including diabetic retinopathy and nephropathy). Cognitive impairment is a well-known complication of DM types 1 and 2; however, its mechanism(s) is(are) not known. We hypothesized that blood-brain barrier (BBB) compromise plays a key role in cognitive decline in DM. Using a DM type 1 model (streptozotocin injected C57BL/6 mice) and type 2 model (leptin knockout obese db/db mice), we showed enhanced BBB permeability and memory loss (Y maze, water maze) that are associated with hyperglycemia. Gene profiling in isolated microvessels from DM type 1 animals demonstrated deregulated expression of 54 genes related to angiogenesis, inflammation, vasoconstriction/vasodilation, and platelet activation pathways by at least 2-fold (including eNOS, TNFα, TGFβ1, VCAM-1, E-selectin, several chemokines, and MMP9). Further, the magnitude of gene expression was linked to degree of cognitive decline in DM type 1 animals. Gene analysis in brain microvessels of DM type 2 db/db animals showed alterations of similar genes as in DM 1 model, some to an even greater extent. Neuropathologic analyses of brain tissue derived from DM mice showed microglial activation, expression of ICAM-1, and attenuated coverage of pericytes compared to controls. There was a significant upregulation of inflammatory genes in brain tissue in both DM models. Taken together, our findings indicate that BBB compromise in DM in vivo models and its association with memory deficits, gene alterations in brain endothelium, and neuroinflammation. Prevention of BBB injury may be a new therapeutic approach to prevent cognitive demise in DM.

Keywords

BBB Endothelial dysfunction Diabetes Dementia Inflammation 

Notes

Acknowledgments

This work was supported in part by NIH research grants AA015913 (YP), MH1106967 (YP), MH65151 (YP), MH115786 (YP), and NS101135 (SR). The authors express their grateful acknowledgement for proofreading and editing to Nancy L. Reichenbach.

Authors’ Contributions

VZR, SG, AS, MW, NAH, MAK, YVB, and AKS—data acquisition and analysis, drafting, revising, and final approval article. SR and YP—conception and design, data acquisition, analysis and interpretation, drafting and revising article, and final approval.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 1.Department of Pathology and Laboratory Medicine, Lewis Katz School of MedicineTemple UniversityPhiladelphiaUSA
  2. 2.Center for Substance Abuse Research, Lewis Katz School of MedicineTemple UniversityPhiladelphiaUSA
  3. 3.Cardiovascular Research Center, Lewis Katz School of MedicineTemple UniversityPhiladelphiaUSA

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