Nutrition for the ageing brain: towards evidence for an optimal diet

As people age they become increasingly susceptible to chronic and extremely debilitating brain diseases. The precise cause of the neuronal degeneration underlying these disorders, and indeed normal brain ageing remains however elusive. Considering the limits of existing preventive methods, there is a desire to develop effective and safe strategies. Growing preclinical and clinical research in healthy individuals or at the early stage of cognitive decline has demonstrated the beneficial impact of nutrition on cognitive functions. The present review is the most recent in a series produced by the Nutrition and Mental Performance Task Force under the auspice of the International Life Sciences Institute Europe (ILSI Europe). The latest scientific advances specific to how dietary nutrients and non-nutrient may affect cognitive ageing are presented. Furthermore, several key points related to mechanisms contributing to brain ageing, pathological conditions affecting brain function, and brain biomarkers are also discussed. Overall, findings are inconsistent and fragmented and more research is warranted to determine the underlying mechanisms and to establish dose-response relationships for optimal brain maintenance in different population subgroups. Such approaches are likely to provide the necessary evidence to develop research portfolios that will inform about new dietary recommendations on how to prevent cognitive decline

Reduced astrocytic differentiation in MRL/MpJ injured spinal cord.

<p>Sagittal sections of the lesion epicenter at 54 dpi (<b>a</b>–<b>l</b>) and 109 dpi (<b>m</b>–<b>r</b>) labeled for BrdU (green) and lineage markers (red): GFAP (<b>a</b>–<b>f</b>), NG2 (<b>g</b>–<b>l</b>), OX-42 (<b>m</b>–<b>r</b>) in C57BL/6 (<b>a</b>–<b>c</b>, <b>g</b>–<b>i</b>, <b>m</b>–<b>o</b>) and MRL/MpJ (<b>d</b>–<b>f</b>, <b>j</b>–<b>l</b>, <b>p</b>–<b>r</b>) mice. Higher magnifications of cells marked by the arrowheads are shown in boxed inserts. <b>s</b>–<b>v</b>, Graphs represent the quantification of BrdU-labeled cells stained for a specific marker at 54 dpi (<b>s</b>, <b>u</b>) and 109 dpi (<b>t</b>, <b>v</b>) shown as percentage of all BrdU-labeled cells (<b>s</b>, <b>t</b>) and as absolute number of co-stained BrdU-labeled nuclei per mm³ (<b>u</b>, <b>v</b>). At 54 dpi, C57BL/6 mice showed more NG2/BrdU- and GFAP/BrdU-positive cells than MRL/MpJ mice. At 109 dpi, C57BL/6 mice had still more GFAP/BrdU-expressing cells than MRL/MpJ mice; however, OX-42/BrdU-positive cells were only found in MRL/MpJ spinal cord (2.7±0.9%). Asterisks denote significant difference between MRL/MpJ and C57BL/6, P<0.05 (Student's t-test). Scale bar, 100 µm (<b>a</b>–<b>i</b>); 50 µm (<b>p</b>–<b>r</b>); 50 µm for boxed area (<b>a</b>–<b>i</b>); 25 µm for boxed area (<b>p</b>–<b>r</b>).</p

Fold changes for the 10 most up- and down-regulated genes in MRL/MpJ compare to C57BL/6 mice after spinal cord hemisection.

<p>The complete data set is available at <a href="http://genechip.salk.edu/rawdata/Thuret_MRL.zip" target="_blank">http://genechip.salk.edu/rawdata/Thuret_MRL.zip</a>.</p><p>Expression changes of genes of interest were also verified by quantitative RT-PCR (Q-PCR). When applicable, the Q-PCR fold changes are presented in brackets [ ].</p

Higher cell proliferation in intact spinal cord but lower increase in cell proliferation after SCI in MRL/MpJ mice.

<p><b>a</b>, <b>b</b>, Immunohistochemical staining for BrdU (arrowheads) on cross sections at the mid-thoracic level of intact spinal cord in C57BL/6 (<b>a</b>) and MRL/MpJ (<b>b</b>) mice 24 h after the last of 6 daily BrdU injections. <b>c</b>, Graphs show the amount of BrdU-labeled nuclei per mm³ in the intact spinal cord at the thoracic level 24 h and 4 weeks after the last BrdU injection. MRL/MpJ mice showed a 1.5× higher level of cell proliferation than C57BL/6. Cell survival was assessed at 4 weeks and there was no significant difference between the two strains. <b>d</b>, Number of BrdU-labeled nuclei per mm³ in the injured spinal cord 1, 54 and 109 dpi. BrdU was injected after injury and for the 6 following days. MRL/MpJ spinal cord showed less cell proliferation at 1 and 54 dpi. <b>e</b>, <b>f</b>, Sagittal sections of the lesion epicenter at 54 dpi stained for BrdU in C57BL/6 (<b>e</b>) and MRL/MpJ (<b>f</b>) mice. Asterisks denote significant difference between MRL/MpJ and C57BL/6, P<0.05 (Student's t-test). Scale bar, 260 µm.</p

Enhanced regeneration of corticospinal tract (CST) axons in MRL/MpJ mice after SCI.

<p><b>a</b>, <b>b</b>, Sagittal sections of BDA-labeled CST axons in C57BL/6 (<b>a</b>) and MRL/MpJ (<b>b</b>) mice. Two weeks after tracing, dorsal hemisections were performed. The CST was analyzed at 4 dpi ( = 18 days after tracing). In both mouse strains, axons are visible rostral and caudal from the injury site. No BDA-labeled fibers were found at the injury site, confirming that the CST was completely transected. <b>c</b>, <b>d</b>, Sagittal sections of BDA-labeled CST axons in injured C57BL/6 (<b>c</b>) and MRL/MpJ (<b>d</b>) mice at 54 dpi. Here, BDA tracing was performed right after SCI. C57BL/6 CST axons retracted from the lesion (arrowhead in <b>c</b>). In contrast, some MRL/MpJ CST fibers crossed through the lesion site (arrowhead in (<b>d</b>)). <b>e</b>, <b>f</b>, Montage of sagittal sections of BDA-labeled CST axons in C57BL/6 (<b>e</b>) and MRL/MpJ (<b>f</b>) mice at 109 dpi. Higher magnifications are shown in <b>g</b> (from boxed area in <b>e</b>) and <b>h</b> (from boxed area in <b>f</b>). We found no BDA-positive fibers below the injury site in C57BL/6 spinal cord (<b>e</b>, <b>g</b>), in contrast to MRL/MpJ mice (<b>f</b>, <b>h</b>). <b>i</b>, <b>j</b>, Data represent percentage of fibers and are reported as a function of the distance from the lesion at 54 dpi (i) and 109 dpi (j). MRL/MpJ mice exhibited significantly more regenerating axons at 0.5 mm caudal from the lesion site. Rostral end of the spinal cord is to the left. The arrows point at the injury site. Asterisks denote significant differences between MRL/MpJ and C57BL/6, P<0.02 (two-way ANOVA, Bonferroni Post-hoc). Scale bar, 250 µm (<b>a</b>–<b>d</b>); 300 µm (<b>e</b>, <b>f</b>); 100 µm (<b>g</b>, <b>h</b>).</p

Enhanced functional recovery after SCI in MRL/MpJ mice.

<p><b>a</b>, The latency to fall off the rotarod is depicted as a function of time for intact (baseline) and injured MRL/MpJ and C57BL/6 mice. In both strains intact mice improved their performance over the course of the 88 days of training, but the C57BL/6 performed better at all time points tested. The injured MRL/MpJ reached their baseline level by the end of the 88 days of testing, whereas the injured C57BL/6 did not. <b>b</b>, Rotarod performance of injured mice is expressed as a ratio of baseline performance. Injured MRL/MpJ performed significantly better than injured C57BL/6 at 12, 18, 53, 60, 67, 74 and 88 dpi (*P<0.002). Injured MRL/MpJ significantly improved between 4 dpi and 88 dpi (#P<0.002), whereas injured C57BL/6 did not improve during that period. <b>c</b>, The number of foot-faults made during grid walking is reported as a function of time for intact (baseline) and injured MRL/MpJ and C57BL/6 mice. Both intact strains improved their ability to cross the grid with fewer foot-faults, but intact MRL/MpJ made more foot-faults throughout the entire training period. The injured MRL/MpJ reached their baseline level already by 12 dpi, whereas the injured C57BL/6 still had not reached their baseline level by the end of the testing period at 18 dpi. <b>d</b>, Grid walking performance of injured mice is expressed as a ratio to baseline performance. Injured MRL/MpJ performed significantly better than injured C57BL/6 at 12 and 18 dpi (p<0.05). Injured MRL/MpJ had significantly improved between 4 dpi and 12 dpi, 18 dpi (p<0.05), whereas injured C57BL/6 did not improve during that period. <b>e</b>, Estimation of bladder fullness is reported as a function of time after SCI in MRL/MpJ and C57BL/6 mice. All MRL/MpJ mice recovered autonomic bladder function by 3 dpi, whereas in C57BL/6 mice, autonomic bladder function did not returned until 6 dpi (Mann Whitney test, p-value = 0.028). Data present mean ± SEM. * denotes significant difference between MRL/MpJ and C57BL/6 and # denotes significant differences in MRL/MpJ performance between time points (P value: two-way ANOVA, Bonferroni post-hoc analysis).</p

P45 reduces FasL-induced cell death signalling.

<p>A. Brain protein extracts from controls and the Thy1-p45 transgenic mice were immunoprecipitated with an anti-p45 or an anti-FADD antibody and followed by immunoblotting with an anti-FADD or an anti-p45 antibody, respectively. The efficiency of immunoprecipitation and expression levels of p45 and FADD were validated with appropriate antibodies as indicated. B. MCF7-hFAS-CTL and MCF7-hFAS-p45 cells were treated with FasL (10 ng/ml) for 0 (–) or 30 (+) min. The lysates were immunoprecipitated with an anti-Fas antibody and followed by immunoblotting with an anti-caspase-8 (Casp-8) antibody. The recruitment of Casp-8 to the DISC is markedly reduced by p45, but not FADD. The efficiency of immunoprecipitation and expression levels of Pro-casp-8, FADD, Fas and p45 were validated with appropriate antibodies as indicated. (C, D) MCF7-hFAS-CTL and MCF7-hFAS-p45 cells were treated with FasL (10 ng/ml) for 0–360 min. The lysates were immunoblotted with an anti-caspase-8 or an anti-PARP antibody. The cleavage of both proteins is markedly attenuated in p45-expressing cells. An anti-actin antibody was used for protein loading control. Closed arrowhead, full-length protein; open arrowhead, cleaved products. (E) FasL- or anti-Fas antibody CH11-treated cells were stained with DAPI to detect shrunken nuclei, indicative of cell death. P45-expressing cells significantly reduced cell death induced by either treatment. ***P<0.001. Data are represented as means ± s.e.m.</p

Representation of the total number of proliferative cells at 1 week and 4 weeks post-transplantation.

<p>Total numbers of Ki67+ (A), Ki67+/Dcx+ (B) and Ki67+/CD11b+ (C) cells per mm³ in the striatum are shown for MCAO/NAC and MCAO/cells groups, one week and four weeks post-transplantation. A) In the absence of cells, the number of proliferative cells in the striatum decreased dramatically between the two time-points (grey volume). In the presence of CTX0E03, the number of Ki67 cells in the striatum decreased more slowly (white volume). B) As for the total number of Ki67+ cells, the numbers of proliferating neuroblasts was maintained by the presence of CTX0E03 (white) as compared to the loss observed in NAC-injected animals (grey). C) Only few microglial cells proliferate at the two time points observed (grey), whereas CTX0E03 cells lead to increased microglial proliferation (white) that decreases with time.</p

Stroke affects the organisation of the dorsal tail of the SVZ.

<p>A) Pictures of the four groups of animals from Protocol 2 are represented (a–d). Pictures in a′, b′, c′ and d′ represent a magnification of the dorsal SVZ from a, b, c and d respectively. B) The volume of the dSVZ was evaluated for each group by stereology; C) The density of Ki67+ cells is shown for each group. NS: Not significant; **: p<0.01; ***: p<0.001.</p

TUNEL assay shows that Thy1-p45 mice have decreased cell death following stab wound injury compared to their WT littermates.

<p>One (A, B) or 3 days (C, D) after stab wound injuries on the right side of T13 spinal cord, Thy1-p45 mice (B, D) had fewer TUNEL⁺ cells compared to their WT littermates (A, C) on the injured side of the spinal cord. Serving as an internal control, there were almost no TUNEL⁺ cells on the contralateral uninjured side of the spinal cord in every section. The TUNEL⁺ cells co-localized with Hoechest 33342 nuclei staining and showed the typical features of cell death (DNA fragmentation and condensation) in the magnified view of injured spinal cord from both Thy1-p45 mice and their WT littermates (E–F). Scale bars: 200 µm (A–D), 20 µm (E, F).</p