Disruption of blood-brain barrier function by chronic intake of saturated fat and cholesterol : implications for Alzheimer’s disease risk

It has been reported that lifestyle including diet is associated with Alzheimer’s disease (AD) risk and progression. Population studies indicate that the chronic consumption of diets enriched in saturated fats (SFA) and cholesterol significantly increase the risk of AD onset and progression. However, the mechanisms underlying the association of AD risk with dietary fat intake are presently unclearProteinaceous deposits enriched in amyloid-β (Aβ) within the cerebral parenchyma (amyloid plaque) and in the cerebrovasculature (cerebral amyloid angiopathy) are the hallmark pathological features of AD. Several animal and cell culture studies suggest that high-fat diets exacerbate amyloidosis by promoting Aβ secretion by neurons and increasing the propensity for oligomerization to occur. However, there is little evidence consistent with cerebral Aβ overproduction in AD. Rather, recent studies in animal models of AD suggest that efflux of Aβ relative to its delivery from the blood is pivotal to cerebral Aβ homeostasis.Two lines of evidence led me to develop the hypothesis that dietary fats may influence AD risk by modulating cerebrovascular exposure to circulating Aβ (Paper1 presented as Literature review of thesis). Firstly, Aβ has potent vasoactive properties and blood vessels treated with exogenous Aβ show substantial structural damage. Moreover, exaggerated plasma Aβ could occur because of chronic ingestion of diets enriched in fats. Dietary SFA were found to significantly increase Aβ abundance within the absorptive cells of small intestine (enterocytes) and thereafter, substantial plasma Aβ remains associated with triglyceride rich lipoproteins (TRLs). It is my contention that cerebrovascular integrity is compromised by the ingestion of fats which increases the plasma concentration of Aβ.An immunohistochemical approach was developed to explore the effects of dietary SFA and cholesterol on cerebrovascular integrity and Aβ kinetics at the bloodbrain barrier (BBB) (Paper 2 presented as Chapter 2 of thesis). Wild-type (WT) mice were used for the dietary intervention studies and appropriate comparisons were made with amyloid precursor protein/presenilin-1 (APP/PS1) amyloid transgenic mice, an established model of AD (Paper 3-5 presented as Chapters 3-5). Critical to the primary scientific objectives, three-dimensional colocalization analysis using double immunofluorescent microscopy was developed (Paper 2). This double immunofluorescent labelling technique enabled the simultaneous detection of two proteins utilizing polyclonal antibodies derived from the same species. Briefly, in order to avoid the cross-reactivity of two polyclonal antibodies that originate from the same species, the concentration of one of the primary antibodies was reduced, so that it was undetectable with conventional secondary antibody methodologies. Rather, avidinbiotin amplification that was specific for the diluted primary antibody was utilized to identify its specific immunoreactivity. The double labelling of proteins with certainty that…