Post-prandial lipid metabolism, lipid-modulating agents and cerebrovascular integrity: Implications for dementia risk

https://doi.org/10.1016/j.atherosclerosissup.2010.04.002Get rights and content

Abstract

Amyloid-β (Aβ) is secreted as an apolipoprotein of nascent triglyceride-rich lipoproteins (TRL) derived from both liver and intestine, but is better recognized as the principal protein component of senile plaque in subjects with Alzheimer's disease. Recent studies suggest that exaggerated exposure to plasma Aβ can compromise cerebrovascular integrity, resulting thereafter in blood to brain delivery of plasma proteins including TRL-Aβ. Parenchymal deposits of Aβ show significant immunoreactivity to apolipoprotein B (apo B), consistent with the notion of lipoprotein-Aβ entrapment. In wild type mice chronically fed physiologically relevant diets, saturated fats (SFA) enhance chylomicron-Aβ concomitant with disturbances in blood–brain barrier integrity. Similarly, dietary cholesterol promotes cerebrovascular extravasation of apo B lipoprotein-Aβ. In this study, we investigated the effects of Atorvastatin, Pravastatin and Probucol on dietary-fat induced disturbances in BBB function. Atorvastatin, a lipid soluble HMG-CoA reductase inhibitor prevented SFA induced parenchymal extravasation of apo B-Aβ at 28 days when incorporated into the diet at 20 mg/kg. In contrast, Pravastatin a water soluble agent had no effect on BBB integrity at an equivalent dose. In cholesterol supplemented mice, Probucol maintained BBB function and extravasation of apo B-Aβ was not evident. The findings suggest that some lipid-modulating agents may be effective in ameliorating the negative effects of saturated fats and cholesterol on cerebrovascular integrity.

Section snippets

Alzheimer's disease, cerebrovasculature and dietary fat link

Alzheimer's disease (AD) is the most common cause of dementia and prevalence is expected to quadruple by the year 2050 [1]. Growing evidence supports the hypothesis that vascular disease risk factors may also contribute to AD onset and progression. Clinical, epidemiological and cross sectional studies have demonstrated a positive association between AD and atherosclerosis [2] and common risk factors include hypercholesterolaemia hypertension, sedentary lifestyle and poor nutrition [3].

Plasma amyloid-beta, dietary lipids and blood–brain barrier integrity

Several studies have provided evidence of a vasoactive role of Aβ, with pathological manifestations prior to Aβ deposition. Furthermore, Aβ is vasoconstrictive and vessels treated with Aβ show significant endothelial cell damage [14]. However, studies where Aβ was intravascularly administered involved acute single injections and investigated transportation across, or sequestration within brain capillaries [15], [16]. Longer term administration of Aβ resulted in a significantly compromised BBB

Apolipoprotein E, triglyceride-rich lipoproteins and blood–brain barrier integrity

Inheriting one or two alleles for apo E4 substantially increases onset and progression of AD, compared to individuals with hetero- or homo-zygous for apo E2 and E3 isoforms. In blood, apo E4 is distributed with remnant lipoproteins that contain relatively more triglycerides (principally chylomicrons), whereas apo E2 and apo E3 tend to be primarily associated with hepatically derived TRL remnants. Studies in apo E knockout mice demonstrate the importance of apo E in maintaining BBB integrity,

Dietary fatty acids and blood–brain barrier integrity

The vasoactive properties of exogenous Aβ led us to explore the hypothesis that dietary SFA increases plasma TRL-Aβ and that with chronic ingestion this consequently leads to parenchymal Aβ accumulation. In a recent study, wild-type mice were fed modified diets enriched in either SFA, MUFA or PUFA fatty acids and compared with low-fat fed controls [27]. Three months after commencement of the lipid enriched diets, there was remarkable cerebral leakage and parenchymal colocalization of Aβ with

Lipid lowering therapy for the prevention and treatment of Alzheimer's disease

The critical observations presented are that dietary saturated fats and cholesterol cause BBB dysfunction, resulting in the blood-to-brain delivery and parenchymal accumulation of apo B lipoprotein-Aβ. If cerebrovascular disturbances are indeed central to AD aetiology and progression, then considering strategies to positively influence integrity is a therapeutic priority. Presently, drug strategies used to treat AD are focussed on maintaining cell–cell communication rather than cerebrovascular

Statins, Alzheimer's and blood–brain barrier integrity

Some, but not all population and clinical studies suggest that statins may reduce AD risk and progression of AD [35], [36]. Possible mechanisms include reduced Aβ secretion; enhanced clearance from blood of apo B lipoproteins; maintenance of BBB function and/or anti-inflammatory properties. Consistent with the latter, Atorvastatin was shown to prevent BBB dysfunction in normolipidaemic spontaneously hypertensive rats [37] and was found to increase plasma anti-oxidant concentration and the

Probucol, Alzheimer's and blood–brain barrier integrity

A recent clinical study using Probucol in elderly AD subjects revealed a stabilisation of cognitive symptoms [38]. Studies in animal models suggest that Probucol could stimulate cerebral efflux of Aβ and suppress of glial activation [39]. In addition, Probucol is a hydrophobic agent delivered into blood in association with chylomicrons. Probucol significantly increases hepatic uptake of TRL's and reduces sub-endothelial entrapment of apo B lipoproteins within arterial intima [40]. The putative

Summary and conclusions

Dementia will become the world's most significant cause of morbidity and mortality within 30 years. Common to AD (the most common form of dementia) and other dementia's is significant cerebrovascular aberrations, characterized by chronic inflammatory processes that compromise tissue integrity and ultimately cognitive function. Presently, there is an arsenal of drugs that notionally could interfere with cerebrovascular inflammation, however few have been methodically considered in this context.

Conflicts of interest

The authors have no conflicts of interest to declare in relation to this article.

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