Bitter brain: Hypoglycemia and the pathology of neurodegeneration and dementia.

Glucose poses the predominant energy source of the brain and its continuous uptake is vital for optimal brain function. Neurons metabolize glucose to generate adenosine triphosphate via glycolysis and the tricarboxylic acid cycle, whereas astrocytes utilize glucose both as an energy source and to generate glutamine - a neurotransmitter precursor- for neurons [Brekke et al., 2015]. Here, we prospectively examine the relationship between chronic hypoglycemia and the associated links between neurodegeneration and dementia. It is proposed that severe episodes or chronic hypoglycemia will induce an increased risk of dementia.A complex and specific literature search was conducted across various scientific, international databases for English, peer-reviewed articles and reviews published in the last two decades using the following terms: diabetes, insulin, glucose metabolism, hypoglycemia, and Alzheimer's disease (AD). Case reports were excluded. The main objectives were predominantly focused on animal- or human-based studies.When blood glucose levels are <55 mg/dL, neurons in the cerebral cortex and hippocampus experience synaptic dysfunction, with neurons in the basal ganglia and thalamus affected in parallel [Mergenthaler et al., 2014]. Evidence shows that chronic hypoglycemia leads to severe neuronal death as well as a significant decline in cognitive performance, spatial learning and memory [Bree et al., 2009; Page et., 2009; Suh et al., 2007]. Hypoglycemia induces oxidative injury in hippocampal dendrites, resulting in impaired synaptic plasticity, reduced MAP2 intensity and thickness in the stratum radiatum of the hippocampal CA1 region and microgliosis in the hippocampus and cerebral cortex [Won, et al., 2012]. A population-based cross-sectional study showed chronic hypoglycemia to have a 2-fold increased risk for developing dementia with poor late-life cognition, independent of premorbid cognition[Yaffe et al., 2013].Recent evidence indicates that chronic hypoglycemia poses a risk factor for dementia, accelerating the progression of tau hyperphosphorylation, Aβ aggregation, cognitive dysfunction and AD. Understanding the pathologic mechanisms of hypoglycemia and monitoring the plasma glucose levels may be key factors in the prevention of AD and dementia.