Abstract
BackgroundSeveral studies have identified use of non-steroidal-anti-inflammatory drugs and statins for prevention of dementia, but their efficacy in slowing progression is not well understood. Cerebrovascular disturbances are common pathological feature of Alzheimer’s disease. We previously reported chronic ingestion of saturated fatty acids (SFA) compromises blood–brain barrier (BBB) integrity resulting in cerebral extravasation of plasma proteins and inflammation. However, the SFA-induced parenchymal accumulation of plasma proteins could be prevented by co-administration of some cholesterol lowering agents. Restoration of BBB dysfunction is clinically relevant, so the purpose of this study was to explore lipid-lowering agents could reverse BBB disturbances induced by chronic ingestion of SFA’s.MethodsWild-type mice were fed an SFA diet for 12 weeks to induce BBB dysfunction, and then randomised to receive atorvastatin, pravastatin or ibuprofen in combination with the SFA-rich diet for 2 or 8 weeks. Abundance of plasma-derived immunoglobulin-G (IgG) and amyloid-β enriched apolipoprotein (apo)-B lipoproteins within brain parenchyme were quantified utilising immunofluorescence microscopy.ResultsAtorvastatin treatment for 2 and 8 weeks restored BBB integrity, indicated by a substantial reduction of IgG and apo B, particularly within the hippocampus. Pravastatin, a water-soluble statin was less effective than atorvastatin (lipid-soluble). Statin effects were independent of changes in plasma lipid homeostasis. Ibuprofen, a lipid-soluble cyclooxygenase inhibitor attenuated cerebral accumulation of IgG and apo B as effectively as atorvastatin. Our findings are consistent with the drug effects being independent of plasma lipid homeostasis.ConclusionOur findings suggest that BBB dysfunction induced by chronic ingestion of SFA is reversible with timely introduction and sustained treatment with agents that suppress inflammation.
Highlights
Several studies have identified use of non-steroidal-anti-inflammatory drugs and statins for prevention of dementia, but their efficacy in slowing progression is not well understood
The saturated fatty acids (SFA) fed mice had a five-fold greater abundance of IgG compared to the low fat (LF)-control mice, with the majority of this accumulation being indicated within the CTX > hippocampal formation (HPF) > BS
Following SFA feeding for 12 weeks, provision of atorvastatin, pravastatin or ibuprofen for 2 weeks generally reduced the total parenchymal IgG abundance, there were differential effects of the agents with respect to efficacy and tissue distribution
Summary
Several studies have identified use of non-steroidal-anti-inflammatory drugs and statins for prevention of dementia, but their efficacy in slowing progression is not well understood. The SFA-induced parenchymal accumulation of plasma proteins could be prevented by co-administration of some cholesterol lowering agents. Population studies have demonstrated that consumption of diets which compromise vascular integrity, such as those enriched in saturated-fatty acids, transfatty acids, or cholesterol are associated with increased risk of AD [3,4,5]. Accumulating evidence suggests that cerebral capillary dysfunction precedes amyloidosis, a hallmark pathological protein marker for Alzheimer’s disease [9]. Common vascular pathological alterations prior to amyloid deposition include a reduction of cerebral capillary endothelial tight junction proteins and increased endothelial pinocytic activity, which in combination result in parenchymal extravasation of plasma proteins within brain parenchyma [10,11,12,13]. Thereafter, deposition of extracellular proteoglycans and collagen reduce arterial distensibility and may cause gross convolutional abnormalities including total capillary collapse with significant alterations in brain blood perfusion [14,15]
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