Title:High Glucose Enhances Neurotoxicity and Inflammatory Cytokine Secretion by Stimulated Human Astrocytes
Volume: 14
Issue: 7
Author(s): Manpreet Bahniwal, Jonathan P. Little and Andis Klegeris*
Affiliation:
- Department of Biology, University of British Columbia Okanagan Campus, 3187 University Way, Kelowna, BC,Canada
Keywords:
Glucose, astrocytes, neuroinflammation, Alzheimer's disease, type 2 diabetes mellitus, Aβ42, hyperglycemia.
Abstract: Background: Chronic neuroinflammation caused by activation of microglia and astrocytes
in the brain contributes to neuronal loss and disease progression in Alzheimer’s disease (AD). Recent
research has identified type 2 diabetes mellitus (T2DM) as a risk factor for AD. High blood glucose
(hyperglycemia) and the phenomenon of insulin resistance are being considered as the major factors
contributing to an increased risk of AD. However, the mechanisms involved in this interaction remain
unclear.
Objective: High glucose has been shown to increase release of pro-inflammatory mediators from various
immune cells, including microglia. Since astrocytes are the most abundant glial cell type in the
brain, we investigated the effects of elevated glucose concentrations (5.5-30.5 mM) on selected functions
of cultured human astrocytes in the presence of inflammatory stimuli.
Method: Experiments were conducted using primary human astrocytes and U-118 MG astrocytoma
cells.
Results: High glucose (30.5 mM) increased mRNA expression of interleukin (IL)-6 and secretion of
both IL-6 and IL-8 by astrocytes. This astrocytic inflammatory response to high glucose did not appear
to be mediated by augmented p38 or p44/42 mitogen activated protein kinase (MAPK) signaling
pathways. In addition, high glucose increased the susceptibility of undifferentiated human SH-SY5Y
neuronal cells and retinoic-acid differentiated SH-SY5Y cells to injury by hydrogen peroxide (H2O2)
and fibrillar amyloid beta-42 protein (Aβ42), respectively.
Conclusion: Our data indicate that hyperglycemia in T2DM may be one of the factors contributing to
the observed increased risk of AD by exacerbating astrocyte-mediated neuroinflammation and neuronal
injury caused by disease-associated agents.
