Role of Retinoid X Receptors (RXRs) and dietary vitamin A in Alzheimer's disease: Evidence from clinicopathological and preclinical studies.

BACKGROUND Vitamin A (VitA), via its active metabolite retinoic acid (RA), is critical for the maintenance of memory function with advancing age. Although its role in Alzheimer's disease (AD) is not well understood, data suggest that impaired brain VitA signaling is associated with the accumulation of β-amyloid peptides (Aβ), and could thus contribute to the onset of AD. METHODS We evaluated the protective action of a six-month-long dietary VitA-supplementation (20 IU/g), starting at 8 months of age, on the memory and the neuropathology of the 3xTg-AD mouse model of AD (n = 11-14/group; including 4-6 females and 7-8 males). We also measured protein levels of Retinoic Acid Receptor β (RARβ) and Retinoid X Receptor γ (RXRγ) in homogenates from the inferior parietal cortex of 60 participants of the Religious Orders study (ROS) divided in three groups: no cognitive impairment (NCI) (n = 20), mild cognitive impairment (MCI) (n = 20) and AD (n = 20). RESULTS The VitA-enriched diet preserved spatial memory of 3xTg-AD mice in the Y maze. VitA-supplementation affected hippocampal RXR expression in an opposite way according to sex by tending to increase in males and decrease in females their mRNA expression. VitA-enriched diet also reduced the amount of hippocampal Aβ40 and Aβ42, as well as the phosphorylation of tau protein at sites Ser396/Ser404 (PHF-1) in males. VitA-supplementation had no effect on tau phosphorylation in females but worsened their hippocampal Aβ load. However, the expression of Rxr-β in the hippocampus was negatively correlated with the amount of both soluble and insoluble Aβ in both males and females. Western immunoblotting in the human cortical samples of the ROS study did not reveal differences in RARβ levels. However, it evidenced a switch from a 60-kDa-RXRγ to a 55-kDa-RXRγ in AD, correlating with ante mortem cognitive decline and the accumulation of neuritic plaques in the brain cortex. CONCLUSION Our data suggest that (i) an altered expression of RXRs receptors is a contributor to β-amyloid pathology in both humans and 3xTg-AD mice, (ii) a chronic exposure of 3xTg-AD mice to a VitA-enriched diet may be protective in males, but not in females

Retinoic Acid Restores Adult Hippocampal Neurogenesis and Reverses Spatial Memory Deficit in Vitamin A Deprived Rats

A dysfunction of retinoid hippocampal signaling pathway has been involved in the appearance of affective and cognitive disorders. However, the underlying neurobiological mechanisms remain unknown. Hippocampal granule neurons are generated throughout life and are involved in emotion and memory. Here, we investigated the effects of vitamin A deficiency (VAD) on neurogenesis and memory and the ability of retinoic acid (RA) treatment to prevent VAD-induced impairments. Adult retinoid-deficient rats were generated by a vitamin A-free diet from weaning in order to allow a normal development. The effects of VAD and/or RA administration were examined on hippocampal neurogenesis, retinoid target genes such as neurotrophin receptors and spatial reference memory measured in the water maze. Long-term VAD decreased neurogenesis and led to memory deficits. More importantly, these effects were reversed by 4 weeks of RA treatment. These beneficial effects may be in part related to an up-regulation of retinoid-mediated molecular events, such as the expression of the neurotrophin receptor TrkA. We have demonstrated for the first time that the effect of vitamin A deficient diet on the level of hippoccampal neurogenesis is reversible and that RA treatment is important for the maintenance of the hippocampal plasticity and function

Dietary polyphenol supplementation prevents alterations of spatial navigation in middle-aged mice

Spatial learning and memory deficits associated with hippocampal synaptic plasticity impairments are commonly observed during aging. Besides, the beneficial role of dietary polyphenols has been suggested as potential functional food candidates to prevent this memory decline. Indeed, polyphenols could potentiate the signaling pathways of synaptic plasticity underlying learning and memory. In this study, spatial learning deficits of middle-aged mice were first highlighted and characterized according to their navigation patterns in the Morris water maze task. An eight-week polyphenol-enriched diet, containing a polyphenol-rich extract from grape and blueberry (PEGB; from the Neurophenols Consortium) with high contents of flavonoids, stilbenes and phenolic acids, was then successful in reversing these age-induced effects. The use of spatial strategies was indeed delayed with aging whereas a polyphenol supplementation could promote the occurrence of spatial strategies. These behavioral results were associated with neurobiological changes: while the expression of hippocampal calmodulin kinase II (CaMKII) mRNA levels was reduced in middle-aged animals, the polyphenol-enriched diet could rescue them. Besides, an increased expression of nerve growth neurotrophic factor (NGF) mRNA levels was also observed in supplemented adult and middle-aged mice. Thus these data suggest that supplementation with polyphenols could be an efficient nutritional way to prevent age-induced cognitive decline

Vitamine A et vieillissement cérébral

To date, convergent data on the role of retinoic acid in the mature brain have established that this molecule, which acts as a hormone, helps to preserve cerebral plasticity by controlling dendritic spine density as well as hippocampal neurogenesis. Deterioration in cerebral plasticity seems to be at the base of the cognitive decline disease. Furthermore, the transcription of several genes, known as muted, in Alzheimer’s patients and whose transcripts are involved in the formation of senile plaques, are controlled by retinoic acid. As seen in other nutrients, aging leads to a lower production of retinoic acid; a phenomenon probably accentuated by the fact that Western populations consume an insufficient amount of vitamin A (60% of the population has a consumption lower than the recommendations). These two phenomena (i.e. level of consumption, the lack of activation of vitamin A) accompanied by important individual differences, would help to explain why some patients have an almost normal aging process, whereas others gradually develop cognitive disorders and then, the disease. A better understanding of the role of a collapse of the retinoid status in the genesis of Alzheimer lesions could, beyond the definition of a preventive nutritional strategy, open therapeutic perspectives, through the use of molecules targeting the nuclear receptors

Apports nutritionnels en acides gras polyinsaturés n-3 et action cellulaire de la vitamine A (effets sur la plasticité cérébrale et la mémoire spatiale chez le rat agé)

Les acides gras polyinsaturés à longue chaîne (AGPI-LC) de la série n-3 jouent des rôles essentiels dans le fonctionnement du cerveau et notamment dans les processus de plasticité synaptique et de mémoire, altérés au cours du vieillissement. Il est maintenant bien admis que ces AGPI peuvent réguler la transcription génique en se liant à des récepteurs nucléaires spécifiques, les PPAR (peroxisome proliferator-activated receptors), mais aussi aux récepteurs de l acide 9-cis rétinoïque, les RXR (retinoid X receptors). En tant que partenaires communs d hétérodimérisation des PPAR et des RAR (récepteurs de l acide tout-trans rétinoïque), les RXR sont des acteurs clés de la modulation de l expression génique par les acides gras et les rétinoïdes. Dans ce contexte, l objectif de ce travail de thèse était d étudier, au cours du vieillissement chez le rat, les effets d une supplémentation en AGPI-LC n-3 sur l activité des voies de signalisation des acides gras et des rétinoïdes, les processus de plasticité cérébrale (plasticité synaptique et neurogenèse) et la mémoire spatiale. Nos principaux résultats montrent qu une supplémentation en AGPI-LC n-3, pendant 21 semaines chez des rats à mi-vie, maintient dans l hippocampe les niveaux d expression des ARNm codant pour RXRg et GAP-43 (protéine synaptique) altérés au cours du vieillissement. De plus les rats âgés supplémentés en AGPI-LC n-3 présentent une augmentation du nombre de néo-neurones hippocampiques et une amélioration de la mémoire spatiale de travail, comparés aux rats âgés contrôle. Les résultats de cette étude plaident en faveur d un effet bénéfique des AGPI-LC n-3 sur la mémoire de travail au cours du vieillissement via notamment, une action sur la plasticité cérébrale. De plus, nos travaux suggèrent l implication des RXR dans l effet neuroprotecteur des AGPI-LC n-3, qui réguleraient l expression de certains gènes cibles impliqués dans la plasticité synaptique et les processus de neurogenèse hippocampique.Long chain polyunsaturated fatty acids (LC-PUFA) of the n-3 series play essential roles in brain functions, including brain plasticity and memory processes which are altered during aging. It is now well accepted that these PUFA regulate gene transcription through binding and activating specific nuclear receptors such as PPAR (peroxisome proliferator-activated receptors) and RXR (retinoid X receptors, which also bind 9-cis retinoic acid). As a common heterodimeric partner of both PPAR and RAR (all-trans retinoic acid receptors), RXR is a key factor in the modulation of gene expression by fatty acids and retinoids. In this context, the purpose of this work was to study the effects of a n-3 LC-PUFA supplementation on fatty acid and retinoid signalling pathways and on cerebral plasticity and spatial memory processes. Our main results show that n-3 LC-PUFA supplementation for 21 weeks in mid-life rats, maintains the mRNA levels of RXRg and GAP-43 (synaptic protein) which were altered in aged rat hippocampus. Besides, supplemented aged rats exhibited increased numbers of newly generated neurons and improved spatial working memory, when compared with control aged rats. To summarize, our results support the neuroprotective effects of n-3 LC-PUFA during aging, in particular on cerebral plasticity and working memory. Furthermore, our works suggest the implication of RXR in the set up of these effects through notably the regulation of some target genes involved in synaptic plasticity and hippocampal neurogenesis processes.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Lipides et vieillissement cérébral

National audienc

Calpaines, protéine kinase C et développement du tissu musculaire

International audienc

Vitamin A, endocrine tissues and hormones: interplay and interactions

Vitamin A (retinol) is a micronutrient critical for cell proliferation and differentiation. In adults, vitamin A and metabolites such as retinoic acid (RA) play major roles in vision, immune and brain functions and tissue remodelling and metabolism. This review presents the physiological interactions of retinoids and endocrine tissues and hormonal systems. Two endocrine systems have been particularly studied. In the pituitary, retinoids target the corticotrophs with a possible therapeutic use in corticotropinomas. In the thyroid, retinoids interfere with iodine metabolism and vitamin A deficiency aggravates thyroid dysfunction caused by iodine-deficient diets. Retinoids use in thyroid cancer appears less promising than expected. Recent and still controversial studies investigated the relations between retinoids and metabolic syndrome. Indeed, retinoids contribute to pancreatic development and modify fat and glucose metabolism. However, more detailed studies are needed before planning any therapeutic use. Finally, retinoids probably play more minor roles in adrenal and gonads development and function apart from their major effects on spermatogenesis

Effects of a n-3 PUFA deficient diet on the expression of retinoid nuclear receptors, neurogranin and neuromodulin in rat brain

A lot of studies performed in rodents revealed that n-3 polyunsaturated fatty acid (PUFA) deficient diets could induce deficits of learning capacities but the mechanisms involved are not well known. Retinoic acid (RA) and its nuclear receptors (RAR and RXR) play a central role in the maintenance of cognitive processes and synaptic plasticity via its action on target genes that are neurogranin (RC3) and neuromodulin (GAP43). Given some interferences were described between the retinoid and fatty acid signaling pathways, we investigated the effects of a _α-linolenic acid (18: 3 n-3) deficient diet on retinoic acid nuclear receptors (RAR, and RXR), on GAP43 and RC3, and on blood and brain fatty acid composition in rats at three times of diet: 3, 9 and 18 weeks. In blood and brain of these animals, we observed a severe n-3 PUFA deficit (18:3 n-3, 20:5 n-3 and particularly 22:6 n-3) associated with an increase in the n-6 PUFA content (mainly 22:5 n-6). Real-time PCR and western blot analysis allowed us to note that retinoid signaling, GAP43 and RC3 expression were affected in the striatum of the n-3 PUFA deprived rats

Effects of a n-3 PUFA deficient diet on the expression of retinoid nuclear receptors, neurogranin and neuromodulin in rat brain

A lot of studies performed in rodents revealed that n-3 polyunsaturated fatty acid (PUFA) deficient diets could induce deficits of learning capacities but the mechanisms involved are not well known. Retinoic acid (RA) and its nuclear receptors (RAR and RXR) play a central role in the maintenance of cognitive processes and synaptic plasticity via its action on target genes that are neurogranin (RC3) and neuromodulin (GAP43). Given some interferences were described between the retinoid and fatty acid signaling pathways, we investigated the effects of a _α-linolenic acid (18: 3 n-3) deficient diet on retinoic acid nuclear receptors (RAR, and RXR), on GAP43 and RC3, and on blood and brain fatty acid composition in rats at three times of diet: 3, 9 and 18 weeks. In blood and brain of these animals, we observed a severe n-3 PUFA deficit (18:3 n-3, 20:5 n-3 and particularly 22:6 n-3) associated with an increase in the n-6 PUFA content (mainly 22:5 n-6). Real-time PCR and western blot analysis allowed us to note that retinoid signaling, GAP43 and RC3 expression were affected in the striatum of the n-3 PUFA deprived rats