Amyloid ß Peptide Compromises Neural Stem Cell Fate by Irreversibly Disturbing Mitochondrial Oxidative State and Blocking Mitochondrial Biogenesis and Dynamics.

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by the accumulation of amyloid ß peptide (Aß). Although most AD mouse models present a decline in neurogenesis, they express mutated genes which regulate neurogenesis per se and are not present in most AD patients, thus masking the real impact of Aß on adult neurogenesis. Mitochondrion, a well-known target of Aß in neurons, is a main regulator of neural stem cell (NSC) fate. Here, we aimed to investigate the impact of Aß on NSC mitochondria and cell fate decisions, namely whether and how Aß affects neurogenesis. NSC fate and mitochondrial parameters, including biogenesis, dynamics, and oxidative stress, were evaluated. Our results showed that Aß impaired NSC viability and proliferation and indirectly blocked neurogenic differentiation, by disrupting mitochondrial signaling of self-renewing NSCs. Importantly, Aß decreased ATP levels, generated oxidative stress, and affected the radical scavenger system through SOD2 and SIRT3. Aß also reduced mtDNA and mitochondrial biogenesis proteins, such as Tfam, PGC-1α, and NRF1, and inhibited activation of PGC-1α-positive regulator CREB. Moreover, Aß triggered mitochondrial fragmentation in self-renewing NSCs and reduced mitochondrial fusion proteins, such as Mfn2 and ERRα. Notably, Aß compromised NSC commitment and survival by irreversibly impairing mitochondria and thwarting any neurogenic rescue through mitochondrial biogenesis, dynamics, or radical scavenger system. Altogether, this study brings new perspective to rethink the molecular targets relevant for endogenous NSC-based strategies in AD.

Tauroursodeoxycholic Acid Enhances Mitochondrial Biogenesis, Neural Stem Cell Pool, and Early Neurogenesis in Adult Rats.

Although neurogenesis occurs in restricted regions of the adult mammalian brain, neural stem cells (NSCs) produce very few neurons during ageing or after injury. We have recently discovered that the endogenous bile acid tauroursodeoxycholic acid (TUDCA), a strong inhibitor of mitochondrial apoptosis and a neuroprotective in animal models of neurodegenerative disorders, also enhances NSC proliferation, self-renewal, and neuronal conversion by improving mitochondrial integrity and function of NSCs. In the present study, we explore the effect of TUDCA on regulation of NSC fate in neurogenic niches, the subventricular zone (SVZ) of the lateral ventricles and the hippocampal dentate gyrus (DG), using rat postnatal neurospheres and adult rats exposed to the bile acid. TUDCA significantly induced NSC proliferation, self-renewal, and neural differentiation in the SVZ, without affecting DG-derived NSCs. More importantly, expression levels of mitochondrial biogenesis-related proteins and mitochondrial antioxidant responses were significantly increased by TUDCA in SVZ-derived NSCs. Finally, intracerebroventricular administration of TUDCA in adult rats markedly enhanced both NSC proliferation and early differentiation in SVZ regions, corroborating in vitro data. Collectively, our results highlight a potential novel role for TUDCA in neurologic disorders associated with SVZ niche deterioration and impaired neurogenesis.

Grape Ripening Is Regulated by Deficit Irrigation/Elevated Temperatures According to Cluster Position in the Canopy.

The impact of water deficit on berry quality has been extensively investigated during the last decades. Nonetheless, there is a scarcity of knowledge on the performance of varieties exposed to a combination of high temperatures/water stress during the growing season and under vineyard conditions. The objective of this research was to investigate the effects of two irrigation regimes, sustained deficit irrigation (SDI, 30% ETc) and regulated deficit irrigation (RDI, 15% ETc) and of two cluster positions within the canopy (east- and west-exposed sides) on berry ripening in red Aragonez (Tempranillo) grapevines. The study was undertaken for two successive years in a commercial vineyard in South Portugal, monitoring the following parameters: pre-dawn leaf water potential, berry temperature, sugars, polyphenols, abscisic acid (ABA) and related metabolites. Additionally, expression patterns for different transcripts encoding for enzymes responsible for anthocyanin and ABA biosynthesis (VviUFGT, VvNCED1, VvßG1, VviHyd1, VviHyd2) were analyzed. In both years anthocyanin concentration was lower in RDI at the west side (RDIW- the hottest one) from véraison onwards, suggesting that the most severe water stress conditions exacerbated the negative impact of high temperature on anthocyanin. The down-regulation of VviUFGT expression revealed a repression of the anthocyanin synthesis in berries of RDIW, at early stages of berry ripening. At full-maturation, anthocyanin degradation products were detected, being highest at RDIW. This suggests that the negative impact of water stress and high temperature on anthocyanins results from the repression of biosynthesis at the onset of ripening and from degradation at later stages. On the other hand, berries grown under SDI displayed a higher content in phenolics than those under RDI, pointing out for the attenuation of the negative temperature effects under SDI. Irrigation regime and berry position had small effect on free-ABA concentration. However, ABA catabolism/conjugation process and ABA biosynthetic pathway were affected by water and heat stresses. This indicates the role of ABA-GE and catabolites in berry ABA homeostasis under abiotic stresses. Principal component analysis (PCA) showed that the strongest influence in berry ripening is the deficit irrigation regime, while temperature is an important variable determining the improvement or impairment of berry quality by the deficit irrigation regime. In summary, this work shows the interaction between irrigation regime and high temperature on the control of berry ripening.

Proanthocyanidin accumulation and biosynthesis are modulated by the irrigation regime in tempranillo seeds.

The main effects of three different irrigation regimes, i.e., sustained deficit irrigation (SDI), regulated deficit irrigation (RDI) and non-irrigated (NI), on seed traits namely proanthocyanidins (PAs) were evaluated in the wine grape cultivar Aragonez (syn. Tempranillo) grown in Alentejo (Portugal) over two growing seasons. Results showed that while the number of seeds per berry was not affected by water availability, seed fresh weight differed among treatments, the NI treatment exhibiting the lowest values. The biosynthetic pathway of flavanols appeared to be modified by the irrigation treatment, and several genes responsible for PA synthesis were up-regulated in the most stressed seeds (RDI and NI). However, this effect had no impact on PA content, suggesting the influence of other factors such as oxidation and/or degradation of PAs at late stages of maturation in grape seeds. The seeds' non-enzymatic antioxidant capacities (oxygen radical absorbance capacity (ORAC) and hydroxyl radical adverting capacity (HORAC)) were modulated by water deficit and correlated well with PA content. The impact of irrigation strategy on PA biosynthesis, content, and anti-radical activity during seed ripening is discussed in the context of increasing interest in the role of PAs in the color and taste of wine, and the potential health benefits relating to their antioxidant capacity.