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Chronic Inflammation as the Mechanistic Link between Type 2 Diabetes Mellitus and Alzheimer's Disease

University of British Columbia

Recent research has identified type 2 diabetes mellitus (T2DM) as a risk factor for neurodegenerative disorders such as Alzheimer’s disease (AD). However, the mechanisms involved in this interaction still remain unclear. Chronic neuroinflammation caused by activation of glial cells in the brain contributes to neuronal loss and disease progression in AD. This thesis investigated if chronic inflammation could be a mechanistic link responsible for increasing the risk of AD in individuals with T2DM. Specifically, I hypothesized that high levels of glucose and the phenomenon of insulin resistance observed in T2DM could accelerate neuronal loss and eventually lead to AD by increasing glial cell activation and/or enhancing neuronal injury caused by disease-specific agents. Since astrocytes are the most abundant glial cell type in the brain, in vitro experiments were conducted using primary human astrocytes and U-118 MG human astrocytic cells as models of primary astrocytes. I found that supernatants of astrocytic cells incubated in high glucose (30.5 mM) were more toxic to neuronal cells pre-treated with high glucose compared to supernatants of astrocytic cells incubated in low glucose (5.5 mM). High glucose increased mRNA expression of the pro-inflammatory cytokine interleukin (IL)-6 and enhanced secretion of both IL-6 and IL-8 by all astrocytic cells. Data obtained indicated that increased activation of the p38 mitogen activated protein kinase (MAPK) may be mediating the effects of high glucose in astrocytic cells. 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 and fibrillar amyloid beta-42 protein (Aβ42), respectively. Human primary glial cells and astroglial cell lines expressed the insulin receptor (INSR) and its signaling components. Moreover, insulin was found to modulate secretion of pro-inflammatory cytokines by primary human astrocytes with 1nM insulin concentration causing maximum enhancement of IL-6 and IL-8 secretion. Therefore, high glucose and insulin levels in T2DM could contribute to an early appearance of AD-like symptoms by increasing glial cell-mediated inflammation. This research highlights novel mechanisms responsible for AD progression and could help identify new preventative and treatment strategies for AD.

Text

2014-07-17

Attribution-NonCommercial-NoDerivs 2.5 Canada

http://hdl.handle.net/2429/48387

Biology

University of British Columbia

UBCO

http://creativecommons.org/licenses/by-nc-nd/2.5/ca/