Differential effects of dietary fatty acids on the cerebral distribution of plasma-derived apo B lipoproteins with amyloid-β

Abstract

Some dietary fats are a risk factor for Alzheimer's disease (AD) but the mechanisms for this association are presently unknown. In the present study we showed in wild-type mice that chronic ingestion of SFA results in blood -brain barrier (BBB) dysfunction and significant delivery into the brain of plasma proteins, including apo B lipoproteins that are endogenously enriched in amyloid-b (Ab). Conversely, the plasma concentration of S100B was used as a marker of brain-to-blood leakage and was found to be increased two-fold because of SFA feeding. Consistent with a deterioration in BBB integrity in SFA-fed mice was a diminished cerebrovascular expression of occludin, an endothelial tight junction protein. In contrast to SFA-fed mice, chronic ingestion of MUFA or PUFA had no detrimental effect on BBB integrity. Utilising highly sensitive three-dimensional immunomicroscopy, we also showed that the cerebral distribution and co-localisation of Ab with apo B lipoproteins in SFA-fed mice are similar to those found in amyloid precursor protein/presenilin-1 (APP/PS1) amyloid transgenic mice, an established murine model of AD. Moreover, there was a strong positive association of plasma-derived apo B lipoproteins with cerebral Ab deposits. Collectively, the findings of the present study provide a plausible explanation of how dietary fats may influence AD risk. Ingestion of SFA could enhance peripheral delivery to the brain of circulating lipoprotein -Ab and exacerbate the amyloidogenic cascade.Alzheimer's disease: Amyloid-b: Blood-brain barrier: SFA: TAG-rich lipoproteins An accumulating body of evidence is consistent with the concept that the onset and progression of Alzheimer's disease (AD) is influenced by lifestyle factors including nutrition (1) . Several population studies have found that SFA are a positive risk factor for AD (2 -3) and in animal models of AD, SFA or cholesterol feeding markedly exacerbates cerebral pathology (4 -5) . However, the mechanisms that link dietary fat to the pathogenesis of AD are unclear.The cerebrovasculature in subjects with AD shows pathological alterations including vascular endothelial and smooth muscle cell proliferation (6) . Blood plasma proteins have been detected in the parenchyma of AD brains (7 -8) and inflammatory sequalae are commonly reported (9 -10) , observations that are consistent with breakdown of the blood-brain barrier (BBB). Yet despite evidence supportive of AD having an underlying vascular component, most research focuses on damage of neurons (11) .A major neuropathological marker of AD is amyloid-b (Ab) deposition in the cerebrovasculature and in the cerebral parenchyma. Derived from amyloid precursor protein (APP), Ab is the predominant component of amyloid plaque (12) . The source of cerebral Ab deposits in AD is uncertain, though there is little evidence for increased cerebral Ab production in sporadic, late-onset AD which accounts for over 96 % of AD cases. Rather, decreased Ab clearance across the BBB via receptor pathways and/or via the choroid plexus h...

Apolipoprotein E does not cross the blood-cerebrospinal fluid barrier, as revealed by an improved technique for sampling CSF from mice

“…By visual inspection, more than 97% of the CSF samples were clear; i.e., appeared to have no blood contamination. This was further evaluated using Western blotting for apoB, a protein found in high concentration in plasma but absent in the central nervous system (CNS) (29). We conducted Western blot analysis using plasma diluted in water, spanning a range of concentrations corresponding to 2.5-0.078%, as standards.…”

“…However, those measurements are not sufficiently sensitive to assess a low level of blood contamination in CSF. Therefore, we used a highly sensitive molecular method to screen for potential blood contamination of the CSF by measuring apoB, a plasma-derived protein that is absent in the CNS (29). As depicted in Fig.…”

Aging-Related Changes in Blood-Brain Barrier Integrity and the Effect of Dietary Fat

“…Digestible energy from the cocoa butter in the SFA diet was 40%, and the main fatty acids in the diet were palmitic (16:0; 5%), stearic (18:0; 7%) and oleic acid (18:1 n-9; 6%; table 1). Eight mice from each group were sacrificed 3, 6 and 12 months after the commencement of dietary treatment, and brain and plasma samples were collected for analysis as described previously [15]. …”

“…One mechanism for the association between dietary fats and AD may be via modulation of BBB function. In genetically unmanipulated mice, chronic ingestion of diets enriched with SFA or cholesterol, but not mono- or polyunsaturated fatty acids, attenuated the expression of endothelial tight junction proteins and resulted in parenchymal extravasation of plasma proteins, including circulating amyloid-β [15]. Ghribi et al [16] made similar findings in wild-type rabbits maintained on cholesterol-supplemented diets and showed amyloid-like plaque pathology, and in amyloid transgenic mice, SFA/cholesterol-enriched diets were shown to significantly exacerbate cerebral amyloidosis [17,18].…”

Probucol Suppresses Enterocytic Accumulation of Amyloid‐β Induced by Saturated Fat and Cholesterol Feeding

“…Subjects with AD have greater apo B lipoprotein-A relative to age matched controls [13] and in transgenic amyloid mice, onset and progression of cerebral amyloidosis is strongly associated with the secretion into and concentration of plasma apo B lipoprotein-A [14]. Apolipoprotein B immunoreactivity is evident in parenchymal amyloid plaque from human cadaver specimens [15] and in A-transgenic mice, cerebral apo B distribution and abundance strongly colocalise with extracellular deposits of A [16], observations consistent with a vascular contribution to disease aetiology.…”