Abstract
Diabetic insulin resistance and pro-diabetic diet are reported to increase dementia risk through unknown mechanisms. Emerging evidence suggests that the integrity of blood-brain barrier (BBB) is central to the onset and progression of neurodegeneration and cognitive impairment. Therefore, the current study investigated the effect of pro-diabetic diets on cognitive dysfunction in association to BBB integrity and its putative mechanisms. In C57BL/6J mice chronically ingested with a diet enriched in fat and fructose (HFF), Morris Water Maze (MWM) test indicated no significant cognitive decline after 4 weeks of HFF feeding compared to low-fat (LF) fed control. However, at this stage, BBB dysfunction accompanied by heightened neuroinflammation in cortex and hippocampal regions was already evident. After 24 weeks, HFF fed mice showed significantly deteriorated cognitive function concomitant with substantial neurodegeneration, which both showed significant associations with increased BBB permeability. In addition, the data indicated that the loss of BBB tight junctions was significantly associated with heightened inflammation and leukocyte infiltration. The data collectively suggest that in mice maintained on pro-diabetic diet, the dysfunctional BBB associated to inflammation and leukocyte recruitment precedes the neurodegeneration and cognitive decline, possibly indicating causal association.
Highlights
Population studies report that type-2 diabetes (T2DM) significantly increases the risk of dementia by ∼5-fold and diabetic insulin resistance is an established risk factor for Alzheimer’s disease (AD; Craft et al, 2000; Bowman et al, 2007, 2012; Barbagallo and Dominguez, 2014; Simó et al, 2017)
The intervention duration of 4 weeks was chosen based on our pilot data, which indicated the onset of mild-insulin resistance, while 24 weeks was to explore the chronic effects of insulin resistance on cognitive function and blood-brain barrier (BBB) permeability
An accumulating body of recent studies suggest that integrity of BBB is pivotal to cognitive decline and dementia risk
Summary
Population studies report that type-2 diabetes (T2DM) significantly increases the risk of dementia by ∼5-fold and diabetic insulin resistance is an established risk factor for Alzheimer’s disease (AD; Craft et al, 2000; Bowman et al, 2007, 2012; Barbagallo and Dominguez, 2014; Simó et al, 2017). General consensus from cross-sectional studies is that cognitive impairment is profoundly associated and induced by hyperglycemia. Recent longitudinal studies report conflicting results showing no agreements between the onset of AD and glucose tolerance (Kawamura et al, 2012). In concert with this disputing finding, McNeilly et al (2012) reported that an improvement of insulin sensitivity by metformin did not ameliorate cognitive dysfunction in a dietary-induced rat model of T2DM. While emerging evidence suggest that dysregulation of neuronal insulin signaling, so-called cerebral insulin resistance, may play central role in cognitive dysfunction (de la Monte, 2012; Ferreira et al, 2014; De Felice and Benedict, 2015; Grillo et al, 2015; Nuzzo et al, 2015), the exact mechanisms by which T2DM influences the cognitive function and dementia risk are yet to be elucidated
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