Abstract
Diabetes mellitus is the most common metabolic disorder characterized by hyperglycemia and associated malfunctions of the metabolism of carbohydrates, proteins, and lipids. There is increasing evidence of a relationship between diabetes and vascular dementia. Interestingly, hyperglycemia-linked neuroinflammation in the central nervous system is considered to play a key role during vascular dementia in diabetic patients. However, the mechanisms responsible for the relationship between hyperglycemia and neuroinflammation is not clearly understood. Diabetes-induced alternations in the blood-brain barrier permit high glucose influx into the brain cells via glucose transporters and promote oxidative stress through overproduction of reactive oxygen species. Despite many studies demonstrating a link between oxidative stress and mitochondrial dysfunction, the relationship between mitochondrial dysfunction and neuron inflammation during hyperglycemia remains to be established. In this review, we will focus on diabetes-induced changes in the central nervous system and the role of mitochondrial heat shock protein 60 (HSP60) as an initiator of oxidative stress and potential modulator of neuroinflammation. We suggest that oxidative stress-mediated mitochondrial dysfunction stimulates the upregulation of mitochondrial heat shock protein 60 (HSP60) and ultimately initiates inflammatory pathways by activating pattern recognition receptors. HSP60 also could be a focal point in the development of a biomarker of neuroinflammation as HSP60 is known to be significantly elevated in diabetic patients. Interestingly, extracellular secretion of HSP60 via exosomes suggests that inflammation could spread to neighboring astrocytes by activating pattern recognition receptors of astrocytes via neuronal exosomes containing HSP60. A mechanism for linking neuron and astrocyte inflammation will provide new therapeutic approaches to modulate neuroinflammation and therefore potentially ameliorate the cognitive impairment in diabetic brains associated with vascular dementia.
Highlights
Emerging findings have uncovered that exosomes are involved with the transport of innate immune receptors such as Toll-like receptor (TLR) 4 and NOD-like receptor 3 (NLRP3) which are responsible for secreting inflammatory mediators which leads to neuroinflammation [77]
heat shock protein 60 (HSP60), a molecular stress protein predominantly found in the mitochondrial matrix, is known to be upregulated and secreted from cells during hyperglycemia-induced mitochondrial stress
There are no reports of hyperglycemia-induced inflammation in the central nervous system through HSP60-activated inflammatory pathways
Summary
Diabetes mellitus is an endocrine disease characterized by hyperglycemia which occurs as a result of the inability of the pancreas to secrete insulin, defects in insulin action, or both [1]. Gestational diabetes is explained as any degree of glucose intolerance that is recognized during pregnancy which resolves on delivery of the placenta [3]. Hyperglycemia results in both microvascular and macrovascular complications which lead to long-term failure of various organs [4]. Atherosclerosis is the formation of cholesterol plaque in the walls of arteries and leads to obstruction of normal blood flow [6]. Arterial macrophages can take up oxidized lipoproteins and stimulate the formation of foam cell which lead to atherogenesis [9]. Ritarwan and coworkers have successfully modeled the occurrence of atherosclerosis in streptozotocin-treated mice with increasing blood glucose and cholesterol level [10]
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