Dietary fats, cerebrovasculature integrity and Alzheimer's disease risk

作者：Takechi R; Galloway S; Pallebage Gamarallage M M S; Lam V; Mamo J C L^*

来源：Progress in Lipid Research, 2010, 49(2): 159-170.

DOI：10.1016/j.plipres.2009.10.004

• Alzheimer's disease
• Amyloid-beta
• Blood-brain barrier
• Cerebrovasculature
• Chylomicrons
• Dietary-fats
• Enterocytes
• Inflammation
• Proteoglycans
• Saturated fatty acids
• Triacylglycerol-rich-lipoproteins

An emerging body of evidence is consistent with the hypothesis that dietary fats influence Alzheimer's disease (AD) risk, but less clear is the mechanisms by which this occurs. Alzheimer's is an inflammatory disorder, many consider in response to fibrillar formation and extracellular deposition of amyloid-beta (A beta). 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 A beta metabolism, or via A beta independent pathways. This review explores these two possibilities taking into consideration; (i) the substantial affinity of A beta for lipids and its ordinary metabolism as an apolipoprotein; (ii) evidence that A beta has potent vasoactive properties and (iii) studies which show that dietary fats modulate A beta biogenesis and secretion. We discuss accumulating evidence that dietary fats significantly influence cerebrovascular integrity and as a consequence altered A beta 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 A beta 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 A beta, consistent with a causal association. Saturated fats and cholesterol may exacerbate A beta induced cerebrovascular disturbances by enhancing exposure of vessels of circulating A beta. 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 A beta. 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 A beta. Rather than being the initiating trigger for inflammation in AD, accumulation of extracellular lipoprotein-A beta 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.

• 出版日期2010-4