Diet is an important lifestyle factor implicated in the etiology of Alzheimer's disease (AD), but so far it is not fully elucidated to which nutrients the suggested protective effect of diet can be attributed. Recent evidence obtained in the amyloid-β 1-42 (Aβ(42)) infusion model in rats has shown that a multi-nutrient intervention known as Fortasyn™ Connect (FC) may protect the central cholinergic system against Aβ(42)-induced toxicity. FC comprises the nutritional precursors and cofactors for membrane synthesis, viz. docosahexaenoic acid (DHA), eicosapentaenoic acid, uridine-mono-phosphate (UMP), choline, phospholipids, folic acid, vitamins B6, B12, C, E, and selenium. In order to investigate whether the combined administration of these nutrients may also affect AD-like pathology, we now evaluated the effects of the FC diet intervention in the transgenic AβPP(swe)/PS1(dE9) mouse model with endogenous Aβ production. In addition we evaluated the effects of diets containing the individual nutrients DHA and UMP and their combination in this model. Between the age of 3 and 6 months, FC diet decreased brain Aβ levels and amyloid plaque burden in the hippocampus of AβPP/PS1 mice. The FC diet also reduced ongoing disintegrative degeneration in the neocortex, as indicated by Amino Cupric Silver staining. Although all three DHA-containing diets were equally effective in changing brain fatty acid profiles, diets differentially affected amyloid-related measures, indicating that effects of DHA may depend on its dietary context. The current data, showing that dietary enrichment with FC reduces AD-like pathology in AβPP/PS1 mice, confirm and extend our previous findings in the Aβ(42) infusion model and favor the combined administration of relevant nutrients.
Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly. Substantial evidence suggests a role for nutrition in the management of AD and especially suggests that interventions with combinations of nutrients are more effective than single-nutrient interventions. The specific multi-nutrient combination Fortasyn™Connect (FC), shown to improve memory in AD, provides phosphatide precursors and cofactors and is designed to stimulate the formation of phospholipids, neuronal membranes, and synapses. The composition comprises nucleotides, omega-3 polyunsaturated fatty acids (n3 PUFA), choline, B-vitamins, phospholipids, and antioxidants. The current study explored the protective properties of FC in a membrane toxicity model of AD, the amyloid-β 1-42 (Aβ42) infused rat, which shows reduced exploratory behavior in an Open Field and impaired cholinergic functioning. To this end, rats were fed an FC enriched diet or a control diet and five weeks later infused with vehicle or Aβ42 into the lateral ventricle. Ten weeks post-infusion Aβ42-rats fed the FC diet showed increased membrane n3 PUFA and phosphatidylcholine content while they did not show the reductions in exploratory behavior or in choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT) immunoreactivity that were seen in Aβ42-rats fed the control diet. We conclude that FC protects the cholinergic system against Aβ42-induced toxicity and speculate that the effects of FC on membrane formation and composition might be supportive for this protective effect. Based on these data a long-term intervention study was started in the prodromal stages of AD (NTR1705, LipiDiDiet, EU FP7).
Research into the development of Alzheimer's disease (AD) provides increasing evidence that vascular risk factors, including high serum cholesterol, might influence the progression of cognitive impairment and neural degeneration. In this study, we investigated the effects of high dietary cholesterol intake and the cholesterol-lowering liver X receptor-agonist T0901317 on capillary density, amyloid-β deposition, and presynaptic boutons in the hippocampus of adult (8 months) and aged (15 months) AβPPswe-PS1dE9 and wild-type mice to elucidate how cholesterol may affect neurodegenerative processes in aging and AD. Our results show increased number of presynaptic boutons in 15-month-old AβPP-PS1 mice compared to age-matched wild-type animals, but no difference at 8 months of age. High cholesterol intake accelerated this response by increasing the amount of presynaptic boutons at 8 and 15 months of age, while T0901317 intake decreased the amount of presynaptic boutons in 15-month-old AβPP-PS1 mice. These findings suggest a synaptic compensatory response to maintain connectivity during aging. We hypothesize that high cholesterol intake may cause impaired cerebral blood flow inducing ischemia, fortifying the above mentioned hypothesis of a compensatory mechanism. Contrarily, cholesterol-lowering agents may positively influence cerebral circulation, thereby diminishing aggravation of AD-like pathology.
J. Neurochem. (2012) 120, 631–640. Abstract Recent evidence indicates that supplementation with a specific combination of nutrients may affect cell membrane synthesis and composition. To investigate whether such nutrients may also modify the physical properties of membranes, and affect membrane‐bound processes involved in signal transduction pathways, we studied the effects of nutrient supplementation on G protein‐coupled receptor activation in vitro. In particular, we investigated muscarinic receptors, which are important for the progression of memory deterioration and pathology of Alzheimer’s disease. Nerve growth factor differentiated pheochromocytoma cells that were supplemented with specific combinations of nutrients showed enhanced responses to muscarinic receptor agonists in a membrane potential assay. The largest effects were obtained with a combination of nutrients known as Fortasyn™ Connect, comprising docosahexaenoic acid, eicosapentaenoic acid, uridine monophosphate as a uridine source, choline, vitamin B6, vitamin B12, folic acid, phospholipids, vitamin C, vitamin E, and selenium. In subsequent experiments, it was shown that the effects of supplementation could not be attributed to single nutrients. In addition, it was shown that the agonist‐induced response and the supplement‐induced enhancement of the response were blocked with the muscarinic receptor antagonists atropine, telenzepine, and AF‐DX 384. In order to determine whether the effects of Fortasyn™ Connect supplementation were receptor subtype specific, we investigated binding properties and activation of human muscarinic M1, M2 and M4 receptors in stably transfected Chinese hamster ovary cells after supplementation. Multi‐nutrient supplementation did not change M1 receptor density in plasma membranes. However, M1 receptor‐mediated G protein activation was significantly enhanced. In contrast, supplementation of M2‐ or M4‐expressing cells did not affect receptor signaling. Taken together, these results indicate that a specific combination of nutrients acts synergistically in enhancing muscarinic M1 receptor responses, probably by facilitating receptor‐mediated G protein activation.
Abstract. The effect of supplementation with the omega 3 polyunsaturated fatty acid (n-3 PUFA) docosahexaenoic acid (DHA) on membrane composition and amyloid-β1−42 (Aβ42) secretion was studied in human amyloid-β protein precursor-transfected Chinese Hamster Ovary (CHO) cells. Twenty-four hour incubation with a range of DHA concentrations resulted in a dosedependent increase in membrane DHA and eicosapentaenoic acid content and a decrease in arachidonic acid content. In addition, DHA supplementation caused a dose-dependent reduction in the secreted Aβ42 levels and resulted in a 4-8 fold decrease in extracellular prostaglandin E2 (PGE2) levels. Tocopherol, which was added to DHA to prevent oxidation, may have contributed to the effect of DHA, since it slightly decreased extracellular Aβ42 and PGE2 levels when given alone. The addition of selective COX-2 inhibitors Celebrex and curcumin to the culture medium resulted in a significant and comparable inhibition of PGE2 release, but did not inhibit Aβ42 secretion, and even significantly increased Aβ42 production in this cell system. Together, the present data show that, whereas both DHA and COX-2 inhibitors may reduce PGE2 production, only DHA in the presence of tocopherol significantly reduced Aβ42 production and concurrently changed membrane lipid composition in CHO cells. It is concluded that in this in vitro setting DHA reduced Aβ42 secretion through membrane-related, but not PGE2-related mechanisms.
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