The GRK2 Overexpression Is a Primary Hallmark of Mitochondrial Lesions during Early Alzheimer Disease

Increasing evidence points to vascular damage as an early contributor to the development of two leading causes of age-associated dementia, namely Alzheimer disease (AD) and AD-like pathology such as stroke. This review focuses on the role of G protein-coupled receptor kinases (GRKs) as they relate to dementia and how the cardio and cerebrovasculature is involved in AD pathogenesis. The exploration of GRKs in AD pathogenesis may help bridge gaps in our understanding of the heart-brain connection in relation to neurovisceral damage and vascular complications of AD. The a priori basis for this inquiry stems from the fact that kinases of this family regulate numerous receptor functions in the brain, myocardium and elsewhere. The aim of this review is to discuss the finding of GRK2 overexpression in the context of early AD pathogenesis. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis through the cerebrovasculature. Finally, we synthesize this newer information in an attempt to put it into context with GRKs as regulators of cellular function, which makes these proteins potential diagnostic and therapeutic targets for future pharmacological intervention

Immunocytochemical Characterization of Alzheimer’s Disease Hallmarks in APP/PS1 Transgenic Mice Treated with a New Anti-Amyloid-β Vaccine

Introduction: APP/PS1 double-transgenic mouse models of Alzheimer’s disease (AD), which overexpress mutated forms of the gene for the human amyloid precursor protein (APP) and presenilin 1 (PS1), have provided robust neuropathological hallmarks of an AD-like pattern at early ages. This study aimed to characterize immunocytochemical patterns of the AD mouse brain, which is treated with the EB101 vaccine, as a model for human AD.Material and methods: In this novel vaccine, a new approach has been taken to circumvent past failures with A? vaccines by judiciously selecting an adjuvant consisting of a physiological matrix embedded in liposomes, composed of naturally occurring phospholipids (phosphatidylcholine, phosphatidylglycerol, and cholesterol).Results: Our findings showed that the administration of amyloid-?1?42 (A?) and sphingosine-1-phosphate emulsified in liposome complex (EB101) to APP/PS1 mice before the onset of A? brain deposition (at 7 weeks of age) and/or at an older age (35 weeks of age) can be effective in both halting the progression and clearing the AD-like neuropathological hallmarks. In addition, passive immunization with EB101 did not activate inflammatory responses from the immune system and astrocytes. Consistent with a decreased inflammatory background, the basal immunological interaction between the T cells and the affected areas (hippocampus) in the brain of treated mice was notably reduced.Conclusion: These results provide strong evidence that immunization with the EB101 vaccine prevents and attenuates AD neuropathology in this type of double-transgenic mice

HTRA1 disaggregates α-synuclein amyloid fibrils and converts them into non-toxic and seeding incompetent species

Parkinson\u27s disease (PD) is closely linked to α-synuclein (α-syn) misfolding and accumulation in Lewy bodies. The PDZ serine protease HTRA1 degrades fibrillar tau, which is associated with Alzheimer\u27s disease, and inactivating mutations to mitochondrial HTRA2 are implicated in PD. Here, we report that HTRA1 inhibits aggregation of α-syn as well as FUS and TDP-43, which are implicated in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. The protease domain of HTRA1 is necessary and sufficient for inhibiting aggregation, yet this activity is proteolytically-independent. Further, HTRA1 disaggregates preformed α-syn fibrils, rendering them incapable of seeding aggregation of endogenous α-syn, while reducing HTRA1 expression promotes α-syn seeding. HTRA1 remodels α-syn fibrils by targeting the NAC domain, the key domain catalyzing α-syn amyloidogenesis. Finally, HTRA1 detoxifies α-syn fibrils and prevents formation of hyperphosphorylated α-syn accumulations in primary neurons. Our findings suggest that HTRA1 may be a therapeutic target for a range of neurodegenerative disorders

Hallazgos histopatológicos en corazón, pulmones y cerebro de ratones expuestos a óxidos de plomo (greta) por vía cutánea.

Introducción: México es un país con grandes depósitos naturales de plomo y se estima que el mundo genera alrededor de 12 a 130,000 toneladas/año y su principal vía de introducción al ambiente es por la atmósfera. El propósito del presente trabajo es identificar si existen lesiones en corazón, pulmones y cerebro después de una exposición cutánea al plomo en ratones.   Material y Métodos: Se seleccionaron 40 ratones sanos: 24 machos y 16 hembras; se les aplicó óxido de plomo (GRETA) por vía cutánea y las dosis fueron de 2,4, 6,8 y 10 mg de óxido de plomo. Se aplicó diario de lunes a sábado, estableciendo 5 lotes de 8 ratones en cada grupo; más un grupo control también de 8 ratones. Cada semana se sacrificó un ratón al azar de cada grupo y 5 ratones fallecieron antes de concluir el experimento. De cada órgano se consignó su coloración, tamaño, aspecto externo, fragilidad del tejido en general, tiempo de exposición al plomo y cambios histopatológicos en los tejidos.   Resultados: En los 40 ratones expuestos se presentó congestión pulmonar en grado moderado, en 33 de ellos (82%) se encontró edema pulmonar de tipo no cardiogénico y en 1 existió coágulo de fibrina. En corazón se presentó congestión vascular moderada en el 97% de los ratones (39 de ellos) y en el 5% (2 ratones) se encontró necrosis leve. En el cerebro las alteraciones fueron edema en todos los ratones expuestos, con necrosis neuronal  en el 88% (35 ratones) y gliosis neuronal reactiva en el 10% (4 ratones), con estas alteraciones los ratones perdieron coordinación en sus movimientos.   Discusión: El presente trabajo mostró que el plomo aplicado por vía cutánea es capaz de absorberse. La mayoría de los mecanismos de toxicidad del plomo han sido estudiados en procesos bioquímicos y afectan sobre todo enzimas en procesos celulares. La frecuencia y la severidad de los síntomas médicos se relaciona con la concentración de plomo en la sangre.   Conclusiones: Por la piel la entrada del plomo inorgánico es mínima, pero el plomo orgánico pasa a través de los folículos pilosos, glándulas sebáceas y sudoríparas directo al torrente sanguíneo. El plomo constituye una parte importante de la contaminación ambiental, el empleo de este metal en la industria, hacen necesario que se controle el impacto negativo de sus acciones tanto en la salud de los seres humanos como en el ambiente.Introducción: México es un país con grandes depósitos naturales de plomo y se estima que el mundo genera alrededor de 12 a 130,000 toneladas/año y su principal vía de introducción al ambiente es por la atmósfera. El propósito del presente trabajo es identificar si existen lesiones en corazón, pulmones y cerebro después de una exposición cutánea al plomo en ratones.   Material y Métodos: Se seleccionaron 40 ratones sanos: 24 machos y 16 hembras; se les aplicó óxido de plomo (GRETA) por vía cutánea y las dosis fueron de 2,4, 6,8 y 10 mg de óxido de plomo. Se aplicó diario de lunes a sábado, estableciendo 5 lotes de 8 ratones en cada grupo; más un grupo control también de 8 ratones. Cada semana se sacrificó un ratón al azar de cada grupo y 5 ratones fallecieron antes de concluir el experimento. De cada órgano se consignó su coloración, tamaño, aspecto externo, fragilidad del tejido en general, tiempo de exposición al plomo y cambios histopatológicos en los tejidos.   Resultados: En los 40 ratones expuestos se presentó congestión pulmonar en grado moderado, en 33 de ellos (82%) se encontró edema pulmonar de tipo no cardiogénico y en 1 existió coágulo de fibrina. En corazón se presentó congestión vascular moderada en el 97% de los ratones (39 de ellos) y en el 5% (2 ratones) se encontró necrosis leve. En el cerebro las alteraciones fueron edema en todos los ratones expuestos, con necrosis neuronal  en el 88% (35 ratones) y gliosis neuronal reactiva en el 10% (4 ratones), con estas alteraciones los ratones perdieron coordinación en sus movimientos.   Discusión: El presente trabajo mostró que el plomo aplicado por vía cutánea es capaz de absorberse. La mayoría de los mecanismos de toxicidad del plomo han sido estudiados en procesos bioquímicos y afectan sobre todo enzimas en procesos celulares. La frecuencia y la severidad de los síntomas médicos se relaciona con la concentración de plomo en la sangre.   Conclusiones: Por la piel la entrada del plomo inorgánico es mínima, pero el plomo orgánico pasa a través de los folículos pilosos, glándulas sebáceas y sudoríparas directo al torrente sanguíneo. El plomo constituye una parte importante de la contaminación ambiental, el empleo de este metal en la industria, hacen necesario que se controle el impacto negativo de sus acciones tanto en la salud de los seres humanos como en el ambiente

Metformin improves healthspan and lifespan in mice

Metformin is a drug commonly prescribed to treat patients with type 2 diabetes. Here we show that long-term treatment with metformin (0.1% w/w in diet) starting at middle age extends healthspan and lifespan in male mice, while a higher dose (1% w/w) was toxic. Treatment with metformin mimics some of the benefits of calorie restriction, such as improved physical performance, increased insulin sensitivity, and reduced LDL and cholesterol levels without a decrease in caloric intake. At a molecular level, metformin increases AMP-activated protein kinase activity and increases antioxidant protection, resulting in reductions in both oxidative damage accumulation and chronic inflammation. Our results indicate that these actions may contribute to the beneficial effects of metformin on healthspan and lifespan. These findings are in agreement with current epidemiological data and raise the possibility of metformin-based interventions to promote healthy aging

Restoring Coastal Plants to Improve Global Carbon Storage: Reaping What We Sow

Long-term carbon capture and storage (CCS) is currently considered a viable strategy for mitigating rising levels of atmospheric CO2 and associated impacts of global climate change. Until recently, the significant below-ground CCS capacity of coastal vegetation such as seagrasses, salt marshes, and mangroves has largely gone unrecognized in models of global carbon transfer. However, this reservoir of natural, free, and sustainable carbon storage potential is increasingly jeopardized by alarming trends in coastal habitat loss, totalling 30–50% of global abundance over the last century alone. Human intervention to restore lost habitats is a potentially powerful solution to improve natural rates of global CCS, but data suggest this approach is unlikely to substantially improve long-term CCS unless current restoration efforts are increased to an industrial scale. Failure to do so raises the question of whether resources currently used for expensive and time-consuming restoration projects would be more wisely invested in arresting further habitat loss and encouraging natural recovery

PAI-1 and functional blockade of SNAI1 in breast cancer cell migration

12 pages, 5 figures.-- PMID: 19055748 [PubMed].-- et al.[Introduction]: Snail, a family of transcriptional repressors implicated in cell movement, has been correlated with tumour invasion. The Plasminogen Activation (PA) system, including urokinase plasminogen activator (uPA), its receptor and its inhibitor, plasminogen activator inhibitor type 1(PAI-1), also plays a key role in cancer invasion and metastasis, either through proteolytic degradation or by non-proteolytic modulation of cell adhesion and migration. Thus, Snail and the PA system are both over-expressed in cancer and influence this process. In this study we aimed to determine if the activity of SNAI1 (a member of the Snail family) is correlated with expression of the PA system components and how this correlation can influence tumoural cell migration.[Methods]: We compared the invasive breast cancer cell-line MDA-MB-231 expressing SNAI1 (MDA-mock) with its derived clone expressing a dominant-negative form of SNAI1 (SNAI1-DN). Expression of PA system mRNAs was analysed by cDNA microarrays and real-time quantitative RT-PCR. Wound healing assays were used to determine cell migration. PAI-1 distribution was assessed by immunostaining.[Results]: We demonstrated by both cDNA microarrays and realtime quantitative RT-PCR that the functional blockade of SNAI1 induces a significant decrease of PAI-1 and uPA transcripts. After performing an in vitro wound-healing assay, we observed that SNAI1-DN cells migrate more slowly than MDA-mock cells and in a more collective manner. The blockade of SNAI1 activity resulted in the redistribution of PAI-1 in SNAI1-DN cells decorating large lamellipodia, which are commonly found structures in these cells.[Conclusions]: In the absence of functional SNAI1, the expression of PAI-1 transcripts is decreased, although the protein is redistributed at the leading edge of migrating cells in a manner comparable with that seen in normal epithelial cells.This work was supported by the CNRS ACI Program "Complexité du vivant" (grant # 050009DR11) and by the Evry Genopole grant "Aide à l'acquisition d'équipement semi-lourd" 2007 and 2008.Peer reviewe

SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass

Increased expression of SIRT1 extends the lifespan of lower organisms and delays the onset of age-related diseases in mammals. Here, we show that SRT2104, a synthetic small molecule activator of SIRT1, extends both mean and maximal lifespan of mice fed a standard diet. This is accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity associated with higher mitochondrial content and decreased inflammation. Short-term SRT2104 treatment preserves bone and muscle mass in an experimental model of atrophy. These results demonstrate it is possible to design a small molecule that can slow aging and delay multiple age-related diseases in mammals, supporting the therapeutic potential of SIRT1 activators in humans

Role of Kinesin Heavy Chain in Crumbs Localization along the Rhabdomere Elongation in Drosophila Photoreceptor

BACKGROUND:Crumbs (Crb), a cell polarity gene, has been shown to provide a positional cue for the extension of the apical membrane domain, adherens junction (AJ), and rhabdomere along the growing proximal-distal axis during Drosophila photoreceptor morphogenesis. In developing Drosophila photoreceptors, a stabilized microtubule structure was discovered and its presence was linked to polarity protein localization. It was therefore hypothesized that the microtubules may provide trafficking routes for the polarity proteins during photoreceptor morphogenesis. This study has examined whether Kinesin heavy chain (Khc), a subunit of the microtubule-based motor Kinesin-1, is essential in polarity protein localization in developing photoreceptors. METHODOLOGY/PRINCIPAL FINDINGS:Because a genetic interaction was found between crb and khc, Crb localization was examined in the developing photoreceptors of khc mutants. khc was dispensable during early eye differentiation and development. However, khc mutant photoreceptors showed a range of abnormalities in the apical membrane domain depending on the position along the proximal-distal axis in pupal photoreceptors. The khc mutant showed a progressive mislocalization in the apical domain along the distal-proximal axis during rhabdomere elongation. The khc mutation also led to a similar progressive defect in the stabilized microtubule structures, strongly suggesting that Khc is essential for microtubule structure and Crb localization during distal to proximal rhabdomere elongation in pupal morphogenesis. This role of Khc in apical domain control was further supported by khc's gain-of-function phenotype. Khc overexpression in photoreceptors caused disruption of the apical membrane domain and the stabilized microtubules in the developing photoreceptors. CONCLUSIONS/SIGNIFICANCE:In summary, we examined the role of khc in the regulation of the apical Crb domain in developing photoreceptors. Since the rhabdomeres in developing pupal eyes grow along the distal-proximal axis, these phenotypes suggest that Khc is essential for the microtubule structures and apical membrane domains during the distal-proximal elongation of photoreceptors, but is dispensable for early eye development

The global abundance of tree palms

Aim Palms are an iconic, diverse and often abundant component of tropical ecosystems that provide many ecosystem services. Being monocots, tree palms are evolutionarily, morphologically and physiologically distinct from other trees, and these differences have important consequences for ecosystem services (e.g., carbon sequestration and storage) and in terms of responses to climate change. We quantified global patterns of tree palm relative abundance to help improve understanding of tropical forests and reduce uncertainty about these ecosystems under climate change. Location Tropical and subtropical moist forests. Time period Current. Major taxa studied Palms (Arecaceae). Methods We assembled a pantropical dataset of 2,548 forest plots (covering 1,191 ha) and quantified tree palm (i.e., ≥10 cm diameter at breast height) abundance relative to co‐occurring non‐palm trees. We compared the relative abundance of tree palms across biogeographical realms and tested for associations with palaeoclimate stability, current climate, edaphic conditions and metrics of forest structure. Results On average, the relative abundance of tree palms was more than five times larger between Neotropical locations and other biogeographical realms. Tree palms were absent in most locations outside the Neotropics but present in >80% of Neotropical locations. The relative abundance of tree palms was more strongly associated with local conditions (e.g., higher mean annual precipitation, lower soil fertility, shallower water table and lower plot mean wood density) than metrics of long‐term climate stability. Life‐form diversity also influenced the patterns; palm assemblages outside the Neotropics comprise many non‐tree (e.g., climbing) palms. Finally, we show that tree palms can influence estimates of above‐ground biomass, but the magnitude and direction of the effect require additional work. Conclusions Tree palms are not only quintessentially tropical, but they are also overwhelmingly Neotropical. Future work to understand the contributions of tree palms to biomass estimates and carbon cycling will be particularly crucial in Neotropical forests