Blood-Brain Barrier Dysfunction Precedes Cognitive Decline and Neurodegeneration in Diabetic Insulin Resistant Mouse Model: An Implication for Causal Link

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.

Knockdown of endogenous circulating C1 inhibitor induces neurovascular impairment, neuroinflammation and cognitive decline

“…It was suggested that blood proteins and neurovascular units are mediators of cognitive impairment [59,60,61]. When we compared cognition between the treated groups, we confirmed a significant impaired cognitive function.…”

Palmitate Is Increased in the Cerebrospinal Fluid of Humans with Obesity and Induces Memory Impairment in Mice via Pro-inflammatory TNF-α

“…obesity and Alzheimer disease (AD), administration of an HFD induces cognitive impairment and accelerates AD pathology (Jeon et al, 2012;Takeda et al, 2010). Moreover, damage to blood-brain barrier permeability as well as increased palmitate levels in the brain have been observed in mice fed an HFD (Spinelli et al, 2017;Takechi et al, 2017).…”

Knockdown of circulating C1 inhibitor induces neurovascular impairment, glial cell activation, neuroinflammation, and behavioral deficits

“…Moreover, emerging evidence correlates cognitive impairment and psychologic behaviors (Cabrera et al, ; Caceda, Griffin, & Delgado, ). It also has been suggested that blood proteins and impairments of the NVU can be mediators of cognitive dysfunction (Mogi & Horiuchi, ; Taheri et al, ; Takechi et al, ). When we compared cognition between the treated mouse groups, we found a significant cognitive deficit in C1INH ASO‐treated mice compared with control mice.…”