ReviewDietary fats, cerebrovasculature integrity and Alzheimer’s disease risk
Introduction
Hallmark pathological characteristics of advanced Alzheimer’s disease (AD) include hyperphosphorylation of the microtubular protein tau in neurons and extracellular deposits of protein that are enriched in the protein amyloid-beta (Aβ) [1], [2]. The formation of tau-tangles results in neuronal synapse dysfunction and eventually loss of cell-cell communication, whereas disturbed Aβ kinetics may be pivotal to pro-inflammatory pathways that compromise cellular integrity [1], [3], [4]. Despite a substantive body of research, it is presently difficult to equivocally delineate if these pathological features of AD are causal or consequential [5], [6], emphasising the therapeutic challenge of identifying the inflammatory triggers that compromise cellular integrity.
Earlier research primarily focussed on the neuronal biogenesis of Aβ in the context that overproduction may initiate formation of fibrillar Aβ deposits and thereafter inflammation [7], [8], [9], [10]. All mutations known to cause AD increases the production of Aβ peptide. However, in sporadic and late onset AD, the most common form of AD, Aβ biosynthesis is comparable to otherwise healthy individuals [11]. Alternatively, insufficient removal of Aβ from cerebrospinal fluid (CSF) has also been proposed as a mechanism for Aβ oligomerization [12], [13], [14]. However, the brain seems potently equipped with substantive efflux processes that would otherwise prevent this. It is estimated that CSF is replenished some three times daily via the choroid plexus and indeed the epithelial cells of the choroid plexus host an array of enzymes which effectively hydrolyse potentially toxic proteins including Aβ [15]. In addition, the endothelial cells of the cerebrovasculature host receptor-proteins that permit reciprocal transfer of Aβ across the blood–brain barrier (BBB) [16], [17], [18], [19], [20]. Collectively, there seems to be exquisite cerebral Aβ homeostatic mechanisms and therefore the concept that cerebral Aβ-overload triggers inflammatory pathways seems physiologically unlikely.
Alzheimer’s disease is a chronic disorder and shares risk factors with other diseases such as non-insulin dependent diabetes and cardiovascular disease (CVD) [21], [22], [23], [24], [25]. However, chronic diseases are often ‘spectrum disorders’ with multiple aetiology. For example, obesity is a major risk factor for diabetes and CVD [26], [27], but not a requisite feature per se and 40% of subjects who experience a coronary event are normolipaemic [26], [27]. Indeed, cholesterol infiltration is not always found in atherosclerotic plaque and there is substantial heterogeneity in the extent of smooth muscle cell proliferation and tissue calcification [28], [29]. Such paradoxes raise the possibility that amyloidosis is simply one of many ‘triggers’ for dementia per se.
Common to chronic disorders, there is ample evidence that lifestyle influences AD risk and progression. Good nutrition, physical activity and environmental enrichment confer synergistic reduction in AD risk [30], [31], [32], [33], [34], [35], [36], [37]. However, in a therapeutic context, less is known of the efficacy of lifestyle interventions on disease progression, perhaps confounded by the diversity of dementia phenotypes. Given that within 20 years the expected global health burden for dementia, of which AD accounts for 80%, will exceed treatment of any other chronic disease [38], [39], [40], exploring lifestyle therapies has become as much an economic imperative as a therapeutic priority.
Most AD research has focused on damage of neurons, however there is an increasing effort to understand the possibility of cerebrovascular dysfunction as a primary risk factor for AD. This paradigm shift is arguably warranted because vascular alterations including endothelial and smooth muscle cell proliferation precede frank amyloidosis [41]. Blood plasma proteins have been detected in the parenchyma of AD brains [42], [43] and inflammatory sequelae are commonly reported [44], [45], observations that are consistent with breakdown of the BBB. Targeting vascular disturbances rather than Aβ deposition may therefore be an appropriate first-focus strategy for prevention and treatment of AD.
It is reasonable to suggest that diet is important in maintaining cerebrovascular integrity [46] particularly given the overwhelming evidence that it contributes substantially to coronary artery health and CVD risk [47], [48], [49], [50], [51], [52], [53]. Population studies also generally support this contention. Saturated fats and cholesterol are both positively associated with AD risk [54], [55], [56], [57], [58], [59], [60] and in animal models, including amyloid transgenic mice, saturated fat (SFA) and cholesterol induce or exacerbate cerebral amyloidoisis [61], [62], [63], [64]. The studies in transgenic amyloid mice are certainly consistent with a vascular contribution to disease over and above exaggerated Aβ biogenesis.
The purpose of this review is to provide contemporary consideration of the mechanisms by which dietary fats influence AD risk. Specifically, this article will focus on the putative interrelationship between plasma lipoproteins, peripheral Aβ kinetics and cerebrovasculature integrity.
Section snippets
Population, clinical and animal model studies
Population studies support a role of dietary fats in AD, although this remains controversial. Laitinen reported that intake of unsaturated fats is protective, whereas intake of saturates increases risk of AD [60]. In the Framingham study, the top quartile of plasma docosahexanoic acid (DHA) (profoundly influenced by diet) was associated with a 47% reduction in risk of all-cause dementia [65]. Strong evidence continues to come from animal studies. Many studies show that cerebral amyloid burden
Receptor mediated cerbrovascular amyloid-beta kinetics
The receptor for advanced glycosylation end products (RAGE) is one endothelial cell protein found to facilitate Aβ transfer from blood-to-brain [16], [17]. However, there is no evidence that TRL or lipoproteins per se bind to RAGE, requiring therefore transfer of Aβ from the lipoprotein particle to the aqueous mileu prior to transport via this pathway. However, in vivo and in vitro studies suggest that Aβ binds tightly to TRL and is not shed or transferred to other chaperone transporters [93],
Triacylglycerol-rich-lipoprotein amyloid-beta-induced cerbrovascular disturbances
It is proposed that post-prandial hyperamyloidemia is one possible mechanism for SFA-induced BBB dysfunction and delivery of TRL-Aβ from blood-to-brain, but presently this remains to be substantiated. Rather, we found that the plasma concentration of Aβ1–40 and Aβ1–42 in SFA-fed mice was similar to mice maintained on either MUFA, PUFA or low-fat (control) diets [106] (Fig. 2). However, caution must be exercised with this interpretation. Post-prandial hyperamyloidemia may not have been apparent
Apolipoprotein E isoforms and Alzheimer’s disease risk
Inheriting one or two alleles for apo E4 increase the risk of AD by 17% and 43%, respectively, compared to individuals hetero- or homo-zygous for apo E2 and E3 isoforms [130]. A number of hypotheses have been put forward for the positive association of AD with apo E4 and reviewed extensively in the literature [92], [131], [132], [133], [134], [135], [136], [137], [138], [139]. Briefly, key concepts include; poorer sequestration of soluble Aβ and hence a propensity for oligomers to form;
Apolipoprotein B association with agrin, perlecan, biglycan and decorin
Proteoglycans are major components of the extracellular matrices, comprised of one or more glycosaminoglycans chains covalently attached to a core protein [166]. Proteoglycans may serve as binding sites for receptors, or as mediators of cell adhesion, migration and proliferation [166]. Studies over the past decade suggest that proteoglycans, in particularly heparin sulfate proteoglycans, contribute towards the formation and thereafter stability of amyloid plaques [167]. However, their putative
Apolipoprotein B isoforms and triacylglycerol-rich-lipoprotein kinetics
In man, hepatically derived TRL can be distinguished from chylomicrons based on the apo B100 and apo B48 isoforms respectively [184], [185]. Apo B48 is synthesized in enterocytes as a consequence of mRNA processing and essentially represents half of the apo B100 amino acid sequence. It’s not clear why this editing process occurs specifically in absorptive epithelial cells of the small intestine of man, suffice to say that this may be responsible for constitutive rates of chylomicron biogenesis
Conclusion
The critical observations considered in this review are that dietary saturated fats and cholesterol cause BBB dysfunction, resulting in the blood-to-brain delivery of apo B lipoprotein-Aβ. In some individuals, dietary-induced disturbances in BBB integrity may be the initiating event for AD. If cerebrovascular disturbances are central to AD aetiology and progression, then considering strategies to positively influence integrity is a therapeutic priority. Presently, drug strategies used to treat
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