J.C.L. Mamo

Dietary fats, cerebrovasculature integrity and Alzheimer's disease risk.

An emerging body of evidence is consistent with the hypothesis that dietary fats influence Alzheimers disease (AD) risk, but less clear is the mechanisms by which this occurs. Alzheimers is an inflammatory disorder, many consider in response to fibrillar formation and extracellular deposition of amyloid-beta (Abeta). Alternatively, amyloidosis could notionally be a secondary phenomenon to inflammation, because some studies suggest that cerebrovascular disturbances precede amyloid plaque formation. Hence, dietary fats may influence AD risk by either modulating Abeta metabolism, or via Abeta independent pathways. This review explores these two possibilities taking into consideration; (i) the substantial affinity of Abeta for lipids and its ordinary metabolism as an apolipoprotein; (ii) evidence that Abeta has potent vasoactive properties and (iii) studies which show that dietary fats modulate Abeta biogenesis and secretion. We discuss accumulating evidence that dietary fats significantly influence cerebrovascular integrity and as a consequence altered Abeta kinetics across the blood-brain barrier (BBB). Specifically, chronic ingestion of saturated fats or cholesterol appears to results in BBB dysfunction and exaggerated delivery from blood-to-brain of peripheral Abeta associated with lipoproteins of intestinal and hepatic origin. Interestingly, the pattern of saturated fat/cholesterol induced cerebrovascular disturbances in otherwise normal wild-type animal strains is analogous to established models of AD genetically modified to overproduce Abeta, consistent with a causal association. Saturated fats and cholesterol may exacerbate Abeta induced cerebrovascular disturbances by enhancing exposure of vessels of circulating Abeta. However, presently there is no evidence to support this contention. Rather, SFA and cholesterol appear to more broadly compromise BBB integrity with the consequence of plasma protein leakage into brain, including lipoprotein associated Abeta. The latter findings are consistent with the concept that AD is a dietary-fat induced phenotype of vascular dementia, reflecting the extraordinary entrapment of peripherally derived lipoproteins endogenously enriched in Abeta. Rather than being the initiating trigger for inflammation in AD, accumulation of extracellular lipoprotein-Abeta may be a secondary amplifier of dietary induced inflammation, or possibly, simply be consequential. Clearly, delineating the mechanisms by which dietary fats increase AD risk may be informative in developing new strategies for prevention and treatment of AD.

Elevated apolipoprotein B‐48 and remnant‐like particle–cholesterol in heterozygous familial hypercholesterolaemia

Apolipoprotein B‐48 (apoB‐48) is a marker of triglyceride‐rich lipoprotein (TRL) remnants of intestinal origin. Chylomicron remnants are causally related to atherosclerosis. We have shown previously that fasting plasma apoB‐48 may predict postprandial lipaemia. Remnant‐like particle–cholesterol (RLP‐C) may also reflect TRL remnants. We aimed to determine whether subjects with heterozygous familial hypercholesterolaemia (FH) had an accumulation of remnants of intestinal origin, as reflected by fasting plasma apoB‐48 and RLP‐C levels.

The effect of metformin and rosiglitazone on postprandial lipid metabolism in obese insulin-resistant subjects

Introduction:  Obese insulin‐resistant individuals exhibit a dyslipidaemia due to raised levels of both hepatically and intestinally derived lipoproteins. However, little is known about the related dysregulation of intestinally derived lipoproteins. We examined whether the insulin‐sensitizing agents, metformin and rosiglitazone, improve intestinal lipoprotein metabolism in obese insulin‐resistant individuals.

Chylomicron amyloid-beta in the aetiology of Alzheimer's disease

Alzheimers disease is characterized by inflammatory proteinaceous deposits comprised principally of the protein amyloid-beta (Abeta). Presently, the origins of cerebral amyloid deposits are controversial, though pivotal for the prevention of Alzheimers disease. Recent evidence suggests that in blood, Abeta may serve as a regulating apoprotein of the triglyceride-rich-lipoproteins and we have found that the synthesis of Abeta in enterocytes and thereafter secretion as part of the chylomicron cascade is regulated by dietary fats. It is our contention that chronically elevated plasma levels of Abeta in response to diets rich in saturated fats may lead to disturbances within the cerebrovasculature and exaggerated blood-to-brain delivery of circulating Abeta, thereby exacerbating amyloidosis. Consistent with this hypothesis we show that enterocytic Abeta is increased concomitant with apolipoprotein B48. Furthermore, cerebral extravasation of immunoglobulin G, a surrogate marker of plasma proteins is observed in a murine model of Alzheimers disease maintained on a saturated-fat diet and there is diminished expression of occludin within the cerebrovasculature, an endothelial tight junction protein.

Three-dimensional colocalization analysis of plasma-derived apolipoprotein B with amyloid plaques in APP/PS1 transgenic mice.

Parenchymal accumulation of amyloid-beta (Aβ) is a hallmark pathological feature of Alzheimer’s disease. An emerging hypothesis is that blood-to-brain delivery of Aβ may increase with compromised blood–brain barrier integrity. In plasma, substantial Aβ is associated with triglyceride-rich lipoproteins (TRLs) secreted by the liver and intestine. Utilizing apolipoprotein B as an exclusive marker of hepatic and intestinal TRLs, here we show utilizing an highly sensitive 3-dimensional immuno-microscopy imaging technique, that in APP/PS1 amyloid transgenic mice, concomitant with substantially increased plasma Aβ, there is a significant colocalization of apolipoprotein B with cerebral amyloid plaque. The findings are consistent with the possibility that circulating lipoprotein-Aβ contributes to cerebral amyloidosis.

A low-protein diet exacerbates postprandial chylomicron concentration in moderately dyslipidaemic subjects in comparison to a lean red meat protein-enriched diet

Objective:To investigate whether altering energy intake as red meat protein or carbohydrate modifies chylomicron homeostasis and postprandial lipaemia.Design:Randomized single-blind dietary intervention trial.Setting:School of Public Health, Division of Health Science, Curtin University, Perth, Western Australia.Subjects:A total of 20 moderately hypertriglyceridaemic but otherwise healthy subjects were recruited and completed the study.Intervention:Participants consumed an isocaloric weight maintenance diet low in protein (14, 53 and 30% of energy as protein, carbohydrate and fat, respectively) or high in protein (25, 35 and 30% energy as protein, carbohydrate and fat) for a period of 6 weeks. Fasting plasma lipids and postprandial lipoprotein studies (triglyceride and apolipoprotein B48) following an oral fat challenge were carried out at the start and conclusion of the dietary intervention period.Results:Consumption of the low- or high-protein diet had no significant effect on fasting plasma or postprandial lipaemia, the latter determined as the incremental area under the triglyceride curve following a fat challenge. However, subjects who consumed a low-protein diet for 6 weeks had a substantially exaggerated postprandial chylomicron response, indicated as the area under the apo B48 curve following a fat challenge. The change in postprandial chylomicron kinetics could not be explained by changes in insulin sensitivity, which appeared to be similar before and after intervention with either diet.Conclusions:Daily moderate consumption of a lean red meat protein-enriched diet attenuates postprandial chylomicronaemia in response to ingestion of a fatty meal.Sponsorship:Meat and Livestock, Australia.

Effect of Simvastatin on markers of triglyceride-rich lipoproteins in familial hypercholesterolaemia.

Background We have previously shown elevated fasting plasma concentrations of intestinal remnants, as reflected by apolipoprotein (apo) B‐48 and remnant‐like particle‐cholesterol (RLP‐C) in patients with heterozygous familial hypercholesterolaemia (FH). We now investigate the effect of an HMG‐CoA reductase inhibitor (simvastatin) on chylomicron remnant metabolism using the measurement of fasting apoB‐48 and RLP‐C in FH patients after long‐ and short‐term simvastatin therapy and after a wash‐out period. We also piloted the response of a breath test, involving the measurement of the fractional catabolic rate (FCR) of an intravenously injected chylomicron remnant‐like emulsion labeled with cholesteryl 13C‐oleate.

The Serum Concentration of the Calcium Binding Protein S100B is Positively Associated with Cognitive Performance in Older Adults.

S100B is a calcium binding peptide produced predominantly by astroglial cells in the central nervous system. S100B paradoxically has neurotrophic and apoptotic effects, dependent on extracellular concentration. This study investigated the relationship between serum S100B levels and neuropsychological performance across a range of cognitive domains in healthy older aged adults. A cohort of 219 participants between the ages of 43 and 84 years (141 female) were recruited. Subjects provided a fasting blood sample for S100B measurement (Mean = 0.24 ng/mL, SD = 0.14) and completed a battery of neuropsychological tests. S100B concentrations (both with and without the covariates of age and sex) were positively associated with the following measures of cognitive performance: digit-symbol coding, Stroop test, and measures of verbal ability. The results from this study show that serum S100B is positively associated with better cognitive performance in healthy older adults.

Effect of an acute hyperinsulinaemic clamp on post‐prandial lipaemia in subjects with insulin resistance

Background  Obese, insulin‐resistant individuals have raised levels of intestinal and hepatic lipoproteins. Insulin decreases the production of hepatic lipoproteins in vivo and so this study aimed to investigate whether an acute hyperinsulinaemic, euglycaemic clamp could correct fasting and post‐prandial dyslipidaemia.