Regular articleNormalization of hippocampal retinoic acid level corrects age-related memory deficits in rats
Graphical abstract
Introduction
Mechanisms of aging and age-related cognitive decline are currently a matter of intense research aiming at defining strategies for maintaining a good cognitive state and quality of life of the elderly. At the cellular and network levels, it is now well established that age-related cognitive impairments are paralleled by a loss of synaptic plasticity in the hippocampus, a key structure for memory processes (Burke and Barnes, 2006, Rosenzweig and Barnes, 2003, Shetty et al., 2017).
Optimal nutrition appears as a promising way to prevent and slow down age-related cognitive decline, without heavy pharmacological intervention. Indeed, it is now recognized that dietary factors, and micronutrients in particular, can act as signaling molecules to maintain brain functions (Gómez-Pinilla, 2008). Among them, vitamin A (vit. A) is of particular interest to maintain cognition along aging (Feart et al., 2005a, Touyarot et al., 2013). Vit. A is a micronutrient provided by animal foods, such as meat and dairy products. It can also be synthesized from carotenoids present in vegetables. In the organism, retinol is metabolized in retinoic acid (RA), its main bioactive derivative, which is implicated in the regulation of a large panel of genes (Blomhoff and Blomhoff, 2006). RA plays crucial roles during development but is also essential at adult age (Olson and Mello, 2010, Shearer et al., 2012, Stoney and McCaffery, 2016). In the brain, RA is notably involved in synaptic plasticity in the hippocampus (Aoto et al., 2008, Arendt et al., 2015a, Chen et al., 2014, Misner et al., 2001).
With aging, vit. A seems to accumulate in the liver, its storage organ (Azaïs-Braesco et al., 1995, Pallet et al., 1997, van der Loo et al., 2004); however, its bioavailability for target tissues appears altered. Supporting this, we previously demonstrated that receptors, transporters, and molecules involved in the signaling pathway of RA in the brain are dysregulated with aging (Enderlin et al., 1997, Pallet et al., 1997, Touyarot et al., 2013). The resulting decrease in RA signaling is associated with impairments of memory performance. In particular, RA signaling in the brain is crucial for spatial and episodic-like memory (Cocco et al., 2002, Etchamendy et al., 2003, Mingaud et al., 2008, Olson and Mello, 2010, Touyarot et al., 2013). Recently, an association between low level of circulating retinol and age-related cognitive decline has also been found in humans (Huang et al., 2018).
As a clue of the causality between RA deficiency and memory impairments, vit. A supplementation in aged rodents was shown to reduce memory impairments (Mingaud et al., 2008, Touyarot et al., 2013). However, mechanisms linking alteration of vit. A metabolism in the liver and hyposignaling of RA pathway in the brain has not been elucidated yet. In addition, the impact on neuronal networks of a reduced brain concentration of RA is poorly understood. Thus, there is no direct evidence for the relationship between the collapse of vit. A metabolism/RA brain bioavailability and age-related cognitive impairment.
In this study, we investigated the mechanisms linking specific alterations of RA metabolism in the hippocampus to memory impairments in aged rats supplemented or not with vit. A. Aging was associated with reduced RA availability and dysregulation of vit. A and RA metabolism in the liver. Importantly, we found a high correlation between hippocampal levels of RA and memory performance. Vit. A supplementation led to a concomitant restoration of the neuronal morphology of pyramidal cells in the hippocampus and of memory capacities altered with aging.
The present work establishes the link between retinoid metabolic collapse and age-related cognitive decline. It highlights the potential capacity of vit. A supplementation to restore memory capacities. This study brings new and useful knowledge on the importance of RA signaling for cognitive processes during aging.
Section snippets
Animals and diet
All experiments were performed in accordance to criteria of the European Communities Council Directive 2010/63/UE and the French National Committee (4184-2016022209565094). Experiments were performed on male Wistar rats obtained from Janvier Labs (France). Young (10 weeks) and old (16 months) rats were maintained under standard housing conditions in a temperature- (23 ± 1 °C) and humidity- (40%) controlled animal room with a 12-h light/dark cycle (0700–1900 hours), with ad libitum access to
RA levels are restored by dietary vit. A in aged rats
Young and 16-month-old rats were fed with either control (5 IU retinol/g) or vit. A supplemented diet (20 IU retinol/g) for 4 weeks. We first assessed the levels of retinol and RA in the serum. Quantitative measurements relied on a purposely designed LC-ESI-MS/MS method using MRM. In accordance with previous reports (Chevalier et al., 1999, Touyarot et al., 2013), a lower retinol concentration was found in the serum of aged rats compared with control rats (young: 1.87 ± 0.01 μM vs. aged: 0.72 ±
Discussion
In summary, our work showed that a vit. A–enriched diet constitutes a powerful strategy for improving hippocampus neuronal network and memory performance in aged rats. In addition, we showed for the first time that memory improvement is directly related to hippocampal RA concentration increase induced by vit. A supplementation.
Acknowledgements
The authors would like to thank the staff from NutriNeuro animal facility and office. The microscopy was done in the Bordeaux Imaging Center, a service unit of the Centre National de la Recherche Scientifique - Institut national de la santé et de la recherche médicale and Bordeaux University, member of the national infrastructure France BioImaging supported by the French National Research Agency (ANR-10-INBS-04). The help of Christel Poujol and Sébastien Marais is acknowledged.
This work was
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2021, Neurobiology of DiseaseCitation Excerpt :To our knowledge, only one study previously highlighted a beneficial effect of chronic retinoic acid (RA) treatment (the active form of VitA) on spatial memory of the 3xTg-AD mice (Lerner et al., 2012), although it has been reported in other murine models of AD (Behairi et al., 2016; Ding et al., 2008; Goncalves et al., 2013). Our results are in line with the literature supporting the advantages of RA signaling stimulation on age-related hippocampal memory deficits, using either dietary or pharmacological VitA administrations (Bonhomme et al., 2014b; Dumetz et al., 2019; Etchamendy et al., 2001; Mingaud et al., 2008; Touyarot et al., 2013). On the other hand, considering the fine regulation of plasmatic retinol (Blomhoff and Blomhoff, 2006; D'Ambrosio et al., 2011; Li et al., 2014; O'Byrne and Blaner, 2013), an excessive VitA supply (i.e. in the absence of VitA deficiency or hyposignaling) can be deleterious and impair memory (Adams, 2010; Crandall et al., 2004; McCaffery et al., 2003; de Oliveira, 2015).
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