Inhibition of RhoA GTPase and the subsequent activation of PTP1B protects cultured hippocampal neurons against amyloid β toxicity

<p>Abstract</p> <p>Background</p> <p>Amyloid beta (Aβ) is the main agent responsible for the advent and progression of Alzheimer's disease. This peptide can at least partially antagonize nerve growth factor (NGF) signalling in neurons, which may be responsible for some of the effects produced by Aβ. Accordingly, better understanding the NGF signalling pathway may provide clues as to how to protect neurons from the toxic effects of Aβ.</p> <p>Results</p> <p>We show here that Aβ activates the RhoA GTPase by binding to p75^NTR, thereby preventing the NGF-induced activation of protein tyrosine phosphatase 1B (PTP1B) that is required for neuron survival. We also show that the inactivation of RhoA GTPase and the activation of PTP1B protect cultured hippocampal neurons against the noxious effects of Aβ. Indeed, either pharmacological inhibition of RhoA with C3 ADP ribosyl transferase or the transfection of cultured neurons with a dominant negative form of RhoA protects cultured hippocampal neurons from the effects of Aβ. In addition, over-expression of PTP1B also prevents the deleterious effects of Aβ on cultured hippocampal neurons.</p> <p>Conclusion</p> <p>Our findings indicate that potentiating the activity of NGF at the level of RhoA inactivation and PTP1B activation may represent a new means to combat the noxious effects of Aβ in Alzheimer's disease.</p

Brain-derived neurotrophic factor prevents dendritic retraction of adult mouse retinal ganglion cells

We used cultured adult mouse retinae as a model system to follow and quantify the retraction of dendrites using diolistic labelling of retinal ganglion cells (RGCs) following explantation. Cell death was monitored in parallel by nuclear staining as ‘labelling’ with RGC and apoptotic markers was inconsistent and exceedingly difficult to quantify reliably. Nuclear staining allowed us to delineate a lengthy time window during which dendrite retraction can be monitored in the absence of RGC death. The addition of brain-derived neurotrophic factor (BDNF) produced a marked reduction in dendritic degeneration, even when application was delayed for 3 days after retinal explantation. These results suggest that the delayed addition of trophic factors may be functionally beneficial before the loss of cell bodies in the course of conditions such as glaucoma

Altered balance of glutamatergic/GABAergic synaptic input and associated changes in dendrite morphology after BDNF expression in BDNF-deficient hippocampal neurons

Cultured neurons from bdnf-/- mice display reduced densities of synaptic terminals, although in vivo these deficits are small or absent. Here we aimed at clarifying the local responses to postsynaptic brain-derived neurotrophic factor (BDNF). To this end, solitary enhanced green fluorescent protein (EGFP)-labeled hippocampal neurons from bdnf-/- mice were compared with bdnf-/- neurons after transfection with BDNF, bdnf-/- neurons after transient exposure to exogenous BDNF, and bdnf+/+ neurons in wild-type cultures. Synapse development was evaluated on the basis of presynaptic immunofluorescence and whole-cell patch-clamp recording of miniature postsynaptic currents. It was found that neurons expressing BDNF::EGFP for at least 16 h attracted a larger number of synaptic terminals than BDNF-deficient control neurons. Transfected BDNF formed clusters in the vicinity of glutamatergic terminals and produced a stronger upregulation of synaptic terminal numbers than high levels of ambient BDNF. Glutamatergic and GABAergic synapses reacted differently to postsynaptic BDNF: glutamatergic input increased, whereas GABAergic input decreased. BDNF::EGFP-expressing neurons also differed from BDNF-deficient neurons in their dendrite morphology: they exhibited weaker dendrite elongation and stronger dendrite initiation. The upregulation of glutamatergic synaptic input and the BDNF-induced downregulation of GABAergic synaptic terminal numbers by postsynaptic BDNF depended on tyrosine receptor kinase B activity, as deduced from the blocking effects of K252a. The suppression of dendrite elongation was also prevented by block of tyrosine receptor kinase B but required, in addition, glutamate receptor activity. Dendritic length decreased with the number of glutamatergic contacts. These results illuminate the role of BDNF as a retrograde synaptic regulator of synapse development and the dependence of dendrite elongation on glutamatergic input

Strategies for the Valorization of Date Fruit and Its Co-Products: A New Ingredient in the Development of Value-Added Foods

Date palm trees (Phoenix dactylifera L.) are traditionally cultivated in South-West Asia and North Africa for date fruit consumption, although in recent years, its consumption has increased worldwide, and its cultivation has spread to other areas of America, sub-Saharan Africa, Oceania, and Southern Europe. During date fruit processing, several types of by-products are generated, such as low-quality dates or seeds, which along with date fruit, represent an excellent source of dietary fiber and bioactive compounds such as flavonoids, tannins, carotenoids, tocopherols, and tocotrienols. Therefore, this review provides information on the processing of dates fruit and the value-added by-products generated from them as well as their applications in different types of foods for the development of foods with an enhanced nutritional and functional profile. The incorporation of date fruit and their co-products in food formulations will help to cover the current consumer demands for foods made with ingredients of natural origin and with health properties beyond the merely nutritional

Date (Phoenix dactylifera L. cv. Medjool) Seed Flour, a Potential Ingredient for the Food Industry: Effect of Particle Size on Its Chemical, Technological, and Functional Properties

The objective of this work was to evaluate the effect of particle size on the chemical composition, fatty acid and polyphenol profile, physicochemical and techno-functional properties, and antioxidant capacity of flour obtained from date seeds. The date seed flours obtained had a high content of total dietary fiber (67.89–76.67 g/100 g), and the reduction in particle size decreased the moisture and protein contents, while the fat, mineral (Ca, Fe, Zn, and Mg), and fatty acid contents were significantly increased, with oleic acid being the highest. Water activity increased with decreasing particle size, and the finest flour (<210 mm) tended to be yellowish and reddish. The water- and oil-holding capacities decreased in the flours with the smallest particle size compared to the largest sizes. The main polyphenolic compounds in all the samples were catechin, epicatechin, and epigallocatechin-3-gallate. The antioxidant activity significantly improved with reductions in the particle size of the date seed flour, with the ABTS, DPPH, and FRAP values ranging between 8.99 and 20.68, 0.66 and 2.35, and 1.94 and 4.91 mg Trolox equivalent/g of date seed flour. The results of the present study suggest that the flour obtained from date seeds cv. Medjool can be a valuable co-product for the food industry due to its fiber content, essential fatty acids, and bioactive compounds that can help reduce the amount of waste generated, promoting the circular economy in the food chain

Quality Characteristics of Fresh Date Palm Fruits of “Medjoul” and “Confitera” cv. from the Southeast of Spain (Elche Palm Grove)

The quality characteristics (physical, techno-functional, and chemical) of date fruits (at the tamar stage) of two cultivars (“Confitera”, autochthonous and unknown vs. “Medjoul”, widely distributed and well-known), grown in the Southeast of Spain (Elche palm grove) were evaluated in order to reinforce decisions aimed at organizing the production of fresh dates from Elche by selecting the most profitable cultivar. Morphologically, Confitera dates were longer and with higher pulp yield than Medjoul dates (4.58 cm vs. 3.88 cm, and 84% vs. 78%, respectively) (p < 0.05). Nutritionally, both dates are a good source of carbohydrates (total sugars (43–48%) and dietary fiber (20–22%)), with small amounts of fat and proteins. The main free sugars in dates from both cultivars were glucose and fructose (reducing sugars). The most abundant mineral found in both date fruits were K, followed by Ca or Mg (depending on the cultivar; Ca in Medjoul and Mg in Confitera). Confitera dates showed a higher total antioxidant activity than Medjoul, corresponding with their higher (p < 0.05) content in polyphenolic compounds, mainly flavonoids (catechin and epicatechin predominantly). Confitera dates should be promoted in this region not only for their contribution to sustainable agricultural development and biodiversity, but also for their higher overall qualit

Modified Wisconsin Card Sorting Test (M-WCST): Normative data for Spanish-speaking pediatric population

OBJECTIVE: To generate normative data for the Modified Wisconsin Card Sorting Test (M-WCST) in Spanish-speaking pediatric populations. METHOD: The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the M-WCST as part of a larger neuropsychological battery. Number of categories, perseverative errors, and total error scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models indicated main effects for age on all scores, such that the number of categories correct increased and total number of perseverative errors and total number of errors decrease linearly as a function of age. Age2 had a significant effect in Chile, Cuba, Ecuador, and Spain for numbers of categories; a significant effect for number of perseverative errors in Chile, Cuba, Mexico, and Spain; and a significant effect for number of total errors in Chile, Cuba, Peru, and Spain. Models showed an effect for MLPE in Cuba (total errors), Ecuador (categories and total errors), Mexico (all scores), Paraguay (perseverative errors and total error), and Spain (categories and total errors). Sex affected number of total errors for Ecuador. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate way to interpret the M-WCST with pediatric populations

Modified Wisconsin Card Sorting Test (M-WCST): Normative data for Spanish-speaking pediatric population

OBJECTIVE: To generate normative data for the Modified Wisconsin Card Sorting Test (M-WCST) in Spanish-speaking pediatric populations. METHOD: The sample consisted of 4,373 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the M-WCST as part of a larger neuropsychological battery. Number of categories, perseverative errors, and total error scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models indicated main effects for age on all scores, such that the number of categories correct increased and total number of perseverative errors and total number of errors decrease linearly as a function of age. Age2 had a significant effect in Chile, Cuba, Ecuador, and Spain for numbers of categories; a significant effect for number of perseverative errors in Chile, Cuba, Mexico, and Spain; and a significant effect for number of total errors in Chile, Cuba, Peru, and Spain. Models showed an effect for MLPE in Cuba (total errors), Ecuador (categories and total errors), Mexico (all scores), Paraguay (perseverative errors and total error), and Spain (categories and total errors). Sex affected number of total errors for Ecuador. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate way to interpret the M-WCST with pediatric populations

Formin1 Mediates the Induction of Dendritogenesis and Synaptogenesis by Neurogenin3 in Mouse Hippocampal Neurons

Neurogenin3, a proneural transcription factor controlled by Notch receptor, has been recently shown to regulate dendritogenesis and synaptogenesis in mouse hippocampal neurons. However, little is known about the molecular mechanisms involved in these actions of Ngn3. We have used a microarray analysis to identify Ngn3 regulated genes related with cytoskeleton dynamics. One of such genes is Fmn1, whose protein, Formin1, is associated with actin and microtubule cytoskeleton. Overexpression of the Fmn1 isoform-Ib in cultured mouse hippocampal neurons induced an increase in the number of primary dendrites and in the number of glutamatergic synaptic inputs at 4 days in vitro. The same changes were provoked by overexpression of Ngn3. In addition downregulation of Fmn1 by the use of Fmn1-siRNAs impaired such morphological and synaptic changes induced by Ngn3 overexpression in neurons. These results reveal a previously unknown involvement of Formin1 in dendritogenesis and synaptogenesis and indicate that this protein is a key component of the Ngn3 signaling pathway that controls neuronal differentiation

Trail Making Test: Normative data for the Latin American Spanish-speaking pediatric population

OBJECTIVE: To generate normative data for the Trail Making Test (TMT) in Spanish-speaking pediatric populations. METHOD: The sample consisted of 3,337 healthy children from nine countries in Latin America (Chile, Cuba, Ecuador, Guatemala, Honduras, Mexico, Paraguay, Peru, and Puerto Rico) and Spain. Each participant was administered the TMT as part of a larger neuropsychological battery. The TMT-A and TMT-B scores were normed using multiple linear regressions and standard deviations of residual values. Age, age2, sex, and mean level of parental education (MLPE) were included as predictors in the analyses. RESULTS: The final multiple linear regression models showed main effects for age on both scores, such that as children needed less time to complete the test while they become older. TMT-A scores were affected by age2 for all countries except, Cuba, Guatemala, and Puerto. TMT-B scores were affected by age2 for all countries except, Guatemala and Puerto Rico. Models indicated that children whose parent(s) had a MLPE >12 years of education needed less time to complete the test compared to children whose parent(s) had a MLPE ≤12 years for Mexico and Paraguay in TMT-A scores; and Ecuador, Mexico, Paraguay, and Spain for TMT-B scores. Sex affected TMT-A scores for Chile, Cuba, Mexico, and Peru, in that boys needed less time to complete the test than girls. Sex did not affect TMT-B scores. CONCLUSIONS: This is the largest Spanish-speaking pediatric normative study in the world, and it will allow neuropsychologists from these countries to have a more accurate approach to interpret the TMT in pediatric populations