Prolonged systemic hyperglycemia does not cause pericyte loss and permeability at the mouse blood-brain barrier

Maarja Andaloussi Mäe,Giacomo Bertuzzi,Elisabeth Raschperger,Guillem Genové,Michael Vanlandewijck,Jennifer J Hofmann,Liqun He,Annika Dalheim,Khayrun Nahar,Christer Betsholtz,Bàrbara Laviña,Tian Li,Annika Keller

doi:10.1038/s41598-018-35576-0

Abstract

Diabetes mellitus is associated with cognitive impairment and various central nervous system pathologies such as stroke, vascular dementia, or Alzheimer’s disease. The exact pathophysiology of these conditions is poorly understood. Recent reports suggest that hyperglycemia causes cerebral microcirculation pathology and blood-brain barrier (BBB) dysfunction and leakage. The majority of these reports, however, are based on methods including in vitro BBB modeling or streptozotocin-induced diabetes in rodents, opening questions regarding the translation of the in vitro findings to the in vivo situation, and possible direct effects of streptozotocin on the brain vasculature. Here we used a genetic mouse model of hyperglycemia (Ins2AKITA) to address whether prolonged systemic hyperglycemia induces BBB dysfunction and leakage. We applied a variety of methodologies to carefully evaluate BBB function and cellular integrity in vivo, including the quantification and visualization of specific tracers and evaluation of transcriptional and morphological changes in the BBB and its supporting cellular components. These experiments did neither reveal altered BBB permeability nor morphological changes of the brain vasculature in hyperglycemic mice. We conclude that prolonged hyperglycemia does not lead to BBB dysfunction, and thus the cognitive impairment observed in diabetes may have other causes.

Highlights

Diabetes mellitus is associated with cognitive impairment and various central nervous system pathologies such as stroke, vascular dementia, or Alzheimer’s disease
It has been suggested that blood-brain barrier (BBB) damage may play a role[5], a hypothesis supported by data from in vitro models of the BBB, as well as animal studies
In the light of novel studies in human diabetes mellitus (DM) patients showing an association with BBB leakage and dementia[14], our study suggests that factors other than hyperglycemia contribute to BBB dysfunction

Summary

Introduction

Diabetes mellitus is associated with cognitive impairment and various central nervous system pathologies such as stroke, vascular dementia, or Alzheimer’s disease. Recent reports suggest that hyperglycemia causes cerebral microcirculation pathology and blood-brain barrier (BBB) dysfunction and leakage The majority of these reports, are based on methods including in vitro BBB modeling or streptozotocininduced diabetes in rodents, opening questions regarding the translation of the in vitro findings to the in vivo situation, and possible direct effects of streptozotocin on the brain vasculature. The Ins2AKITA mouse constitutes a clear advance over chemically-induced DM, as the primary insult is beta cell-specific This mouse model is stable and reproducible and allows longitudinal studies of hyperglycemia complications. We analyzed whether hyperglycemia leads to transcriptional or morphological changes in the mouse brain microvasculature These methods failed to demonstrate increased BBB permeability in Ins2AKITA mice

Methods

Results

Conclusion