Post-prandial lipid metabolism, lipid-modulating agents and cerebrovascular integrity: Implications for dementia risk
Section snippets
Alzheimer's disease, cerebrovasculature and dietary fat link
Alzheimer's disease (AD) is the most common cause of dementia and prevalence is expected to quadruple by the year 2050 [1]. Growing evidence supports the hypothesis that vascular disease risk factors may also contribute to AD onset and progression. Clinical, epidemiological and cross sectional studies have demonstrated a positive association between AD and atherosclerosis [2] and common risk factors include hypercholesterolaemia hypertension, sedentary lifestyle and poor nutrition [3].
Plasma amyloid-beta, dietary lipids and blood–brain barrier integrity
Several studies have provided evidence of a vasoactive role of Aβ, with pathological manifestations prior to Aβ deposition. Furthermore, Aβ is vasoconstrictive and vessels treated with Aβ show significant endothelial cell damage [14]. However, studies where Aβ was intravascularly administered involved acute single injections and investigated transportation across, or sequestration within brain capillaries [15], [16]. Longer term administration of Aβ resulted in a significantly compromised BBB
Apolipoprotein E, triglyceride-rich lipoproteins and blood–brain barrier integrity
Inheriting one or two alleles for apo E4 substantially increases onset and progression of AD, compared to individuals with hetero- or homo-zygous for apo E2 and E3 isoforms. In blood, apo E4 is distributed with remnant lipoproteins that contain relatively more triglycerides (principally chylomicrons), whereas apo E2 and apo E3 tend to be primarily associated with hepatically derived TRL remnants. Studies in apo E knockout mice demonstrate the importance of apo E in maintaining BBB integrity,
Dietary fatty acids and blood–brain barrier integrity
The vasoactive properties of exogenous Aβ led us to explore the hypothesis that dietary SFA increases plasma TRL-Aβ and that with chronic ingestion this consequently leads to parenchymal Aβ accumulation. In a recent study, wild-type mice were fed modified diets enriched in either SFA, MUFA or PUFA fatty acids and compared with low-fat fed controls [27]. Three months after commencement of the lipid enriched diets, there was remarkable cerebral leakage and parenchymal colocalization of Aβ with
Lipid lowering therapy for the prevention and treatment of Alzheimer's disease
The critical observations presented are that dietary saturated fats and cholesterol cause BBB dysfunction, resulting in the blood-to-brain delivery and parenchymal accumulation of apo B lipoprotein-Aβ. If cerebrovascular disturbances are indeed central to AD aetiology and progression, then considering strategies to positively influence integrity is a therapeutic priority. Presently, drug strategies used to treat AD are focussed on maintaining cell–cell communication rather than cerebrovascular
Statins, Alzheimer's and blood–brain barrier integrity
Some, but not all population and clinical studies suggest that statins may reduce AD risk and progression of AD [35], [36]. Possible mechanisms include reduced Aβ secretion; enhanced clearance from blood of apo B lipoproteins; maintenance of BBB function and/or anti-inflammatory properties. Consistent with the latter, Atorvastatin was shown to prevent BBB dysfunction in normolipidaemic spontaneously hypertensive rats [37] and was found to increase plasma anti-oxidant concentration and the
Probucol, Alzheimer's and blood–brain barrier integrity
A recent clinical study using Probucol in elderly AD subjects revealed a stabilisation of cognitive symptoms [38]. Studies in animal models suggest that Probucol could stimulate cerebral efflux of Aβ and suppress of glial activation [39]. In addition, Probucol is a hydrophobic agent delivered into blood in association with chylomicrons. Probucol significantly increases hepatic uptake of TRL's and reduces sub-endothelial entrapment of apo B lipoproteins within arterial intima [40]. The putative
Summary and conclusions
Dementia will become the world's most significant cause of morbidity and mortality within 30 years. Common to AD (the most common form of dementia) and other dementia's is significant cerebrovascular aberrations, characterized by chronic inflammatory processes that compromise tissue integrity and ultimately cognitive function. Presently, there is an arsenal of drugs that notionally could interfere with cerebrovascular inflammation, however few have been methodically considered in this context.
Conflicts of interest
The authors have no conflicts of interest to declare in relation to this article.
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Niacin mitigates blood–brain barrier tight junctional proteins dysregulation and cerebral inflammation in ketamine rat model of psychosis: Role of GPR109A receptor
2022, Progress in Neuro-Psychopharmacology and Biological PsychiatryCitation Excerpt :The ability of niacin to restore BBB integrity in ketamine-injected rats was confirmed histopathologically and could be attributed to the profound anti-inflammatory properties of niacin. Several in vivo and in vitro studies suggest that pharmacological agents with anti-inflammatory activity may positively regulate BBB integrity through regulation of systemic inflammatory pathways (Kalayci et al., 2005; Ifergan et al., 2006; Pallebage-Gamarallage et al., 2010; Pallebage-Gamarallage et al., 2012; Takechi et al., 2013a). One of the proteins implicated in the maintenance of BBB integrity and functioning is MMP9.
Dietary modulators of statin efficacy in cardiovascular disease and cognition
2014, Molecular Aspects of MedicineCitation Excerpt :The lipophilic statins also reversed HFD-induced changes in the brain biochemical levels (p < 0.05), but administration of the hydrophilic statin did not. Similarly, another study has shown that the lipophilic atorvastatin (20 mg/kg), but not the hydrophilic pravastatin (equipotent dose), protected the blood–brain barrier from chronic high-saturated-fat diet (20%, w/w for 90 days) induced disturbances in wild type mice as qualitatively demonstrated by extravasation of plasma protein immunoglobulin G within the cerebral tissue (Pallebage-Gamarallage et al., 2010). There has been at least one study, however, that has shown some neural benefit from a hydrophilic statin.
Succinobucol versus probucol: Higher efficiency of succinobucol in mitigating 3-NP-induced brain mitochondrial dysfunction and oxidative stress in vitro
2013, MitochondrionCitation Excerpt :As mentioned previously, mitochondrial damage and oxidative stress mediate the neurodegeneration observed in HD (Damiano et al., 2010; Mochel and Haller, 2011; Oliveira, 2010). On the other hand, probucol and succinobucol have anti-inflammatory and antioxidant properties (Kunsch et al., 2004; Pallebage-Gamarallage et al., 2010) and the pattern compound has been reported to present neuroprotective effects in experimental models (Colle et al., 2012; Farina et al., 2009; Park et al., 2007; Santos et al., 2012). However, there is a lack of evidence concerning the potential protective effect of succinobucol in experimental models of neurotoxicity/neuropathology in the literature.
Probucol, a lipid-lowering drug, prevents cognitive and hippocampal synaptic impairments induced by amyloid β peptide in mice
2012, Experimental NeurologyCitation Excerpt :Furthermore, clinical studies suggest that statins, which are the most potent agents for reduction of serum cholesterol (Gotto, 2002), via HMG-CoA reductase inhibition (Miida et al., 2007), may reduce risk and progression of AD (Haag et al., 2009). Possible additional mechanisms associated with these effects of statins include their “pleiotropic” effects, related to the modulation of inflammatory, vascular and immunological events (Kalayci et al., 2005; Pallebage-Gamarallage et al., 2010). Of particular importance, a recent study showed that atorvastatin prevented hippocampal cell death, neuroinflammation and oxidative stress induced by intracerebroventricular (i.c.v.) administration of aggregated Aβ1–40 in mice (Piermartiri et al., 2010), suggesting that statins not only prevent Aβ aggregation (as reported by Longenberger and Shah, 2011), but also play protective effects by decreasing the toxicity induced by aggregated Aβ.
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