Characterizing blood–brain barrier perturbations after exposure to human triglyceride‐rich lipoprotein lipolysis products using MRI in a rat model

Abstract

Purpose Previous studies indicated hyperlipidemia may be a risk factor for Alzheimer’s disease, but the contributions of postprandial triglyceride-rich lipoprotein (TGRL) are not known. In this study, changes in blood-brain barrier diffusional transport following exposure to human TGRL lipolysis products were studied using MRI in a rat model. Methods Male Sprague-Dawley rats (~180–250 g) received an i.v. injection of lipoprotein lipase (LpL)-hydrolyzed TGRL (n=8, plasma concentration ≈ 150 mg human TGRL /dL). Controls received i.v. injection of either Saline (n=6) or LpL only (n=6). The 1H longitudinal relaxation rate R1=1/T1 was measured over 18 minutes using a rapid-acquired refocus-echo (RARE) sequence after each of 3 injections of the contrast agent Gd-DTPA. Patlak plots were generated for each pixel yielding blood-to-brain transfer coefficients, Ki, chosen for best fit to impermeable, uni-directional influx or bi-directional flux models using the F-test. Results Analysis from a 2-mm slice 2 mm rostral to the bregma showed a 275% increase of mean Ki during the first 20 minutes after infusion of human TGRL lipolysis product that differed significantly compared to saline and LpL controls. This difference disappeared by 40 minutes mark. Conclusion These results suggest human TGRL lipolysis products can lead to a transient increase in rat BBB permeability. (199 words)

Triglyceride-rich lipoprotein lipolysis products increase blood-brain barrier transfer coefficient and induce astrocyte lipid droplets and cell stress

“…Our earlier studies and those of others have demonstrated that the BBB transfer coefficient (K i ) in rats can be altered by diet, obesity, and/or TGRL lipolysis infusion (12,47). Our studies are the first to model the postprandial state after a single meal in mice and show increased BBB K i in as little as 20 min following TGRL lipolysis infusion and that this coefficient subsequently falls significantly to a level not significantly different from baseline within 40 min.…”

“…Gd-contrast agent extravasation is a validated and highly precise technique for measuring increases in brain transfer coefficient (K i ϭ permeability ϫ surface area/volume) in human and rodent studies (17,30,36,48,50,66). Here we used a similar MRI methodology (47,61) to measure alterations in BBB K i by measuring extravasation of gadolinium contrast agent and found a transient increase with TGRL lipolysis treatment. The transient nature of the change in K i (i.e., the fall in K i following the initial increase after TGRL lipolysis product infusion) remains to be investigated.…”

“…Endothelial cells and astrocytes work together to limit paracellular and transcellular transport from blood to brain (1,29,57). Previously, the BBB was believed to be a relatively static, low-permeability barrier for blood-brain transfer; however, recent work indicates that this barrier is much more dynamic than previously thought (47).…”

Reduced cognitive function, increased blood-brain-barrier transport and inflammatory responses, and altered brain metabolites in LDLr -/-and C57BL/6 mice fed a western diet

“…Even though under normal conditions the blood-brain barrier (BBB) is highly regulated, metabolic stresses such as hyperlipidemia can cause neurovascular unit dysfunction and increase BBB permeability [ 62 ]. Studies by our lab have demonstrated that a bolus infusion of TGRL lipolysis products, similar to an increase that would be found in the postprandial state, can lead to a transient increase in the BBB Gd-DTPA transfer coefficient (Ki) [ 17 , 63 ]. Here Ki was increased in animals fed a WD, while cerebral blood flow, determined by perfusion weighted imaging, was essentially normal.…”

Blood-brain barrier dysfunction and recovery after ischemic stroke

“…This remodeling may be mediated at least in part by MMP-9, as HFD induces similar level of obesity, hyperglycemia and hyperlipidemia in MMP-9 −/− mice, but there is no cerebrovascular remodeling (Deng et al, 2014). Acute injection of human triglyceride-rich lipoprotein, which releases lipolysis products upon hydrolysis, increases BBB permeability in rats within 20 min (Ng et al, 2016). Exactly how hyperlipidemia leads to BBB dysfunction remains largely unknown, although oxidative stress may play a role (Dias et al, 2014).…”