Age-dependent changes in TDP-43 levels in a mouse model of Alzheimer disease are linked to Aβ oligomers accumulation

<p>Abstract</p> <p>Background</p> <p>Transactive response DNA-binding protein 43 (TDP-43) is the pathological protein found in frontotemporal lobar degeneration with ubiquitin positive inclusions and in amyotrophic lateral sclerosis. In diseased tissue, TDP-43 translocates from its physiological nuclear location into the cytoplasm, where it accumulates. Additionally, C-terminal fragments of TDP-43 accumulate in affected brain regions and are sufficient to cause TDP-43 mislocalization and cytoplasmic accumulation <it>in vitro</it>. TDP-43 also accumulates in 30% of Alzheimer disease (AD) cases, a finding that has been highly reproducible. The role of TDP-43 in AD and its relation with Aβ and tau pathology, the two neuropathological hallmarks of AD, remains to be elucidated.</p> <p>Results</p> <p>Here we show that levels of TDP-43 and its ~35 kDa C-terminal fragment are significantly increased in the 3×Tg-AD mice, an animal model of AD that develops an age-dependent cognitive decline linked to the accumulation of Aβ and tau. We also report that the levels of TDP-43 and its C-terminal fragment correlate with the levels of soluble Aβ oligomers, which play a key role in AD pathogenesis. Notably, genetically reducing Aβ₄₂production restores the levels of TDP-43 and its ~35 kDa C-terminal fragment to control levels.</p> <p>Conclusions</p> <p>These data suggest a possible relation between Aβ oligomers and TDP-43.</p

Marine climate change and environmental indicators from the Marine Core Service

In the framework of the Mediterranean Operational Oceanography Network (MOON, http://www.moon-oceanforecasting.eu) The Mediterranean Forecasting System (Pinardi et al., 2003) has started the design and development of services that include the routine production of environmental and climate indicators. A process of identifying user requirements has been started in collaboration with European Environment Agency and the indicators definition and implementation aim to take user requirements into account. The indicators are extensively used by EEA (EEA web page on indicators: http://themes.eea.europa.eu/indicators/). INGV has carried out an analysis on the possible improvements of existing indicators in use by EEA and on the development of new indicators based on Marine Core Services (MCS) products. The list of indicators includes: Temperature, Chlorophyll-a (from ocean colour), Ocean Currents and Transport, Salinity, Transparency, Sea Level, Sea Ice and Density. A critical analysis has been carried out to identify the relevance of the above-mentioned indicators for EU policies, their spatial and temporal coverage, their accuracy and their availability (Coppini et al., 2008). INGV in collaboration with CNR-ISAC are directly involved on the development of the indicators in the Mediterranean region and European Seas region the Temperature and Chlorophyll-a (Chl-a) products are the most suitable for an indicator development test phase. In particular the OO Chl-a product, deduced from satellite data, is able to contribute to the further development of the EEA Chl-a indicator on eutrohpication that is based on in-situ measurements (CSI023). For this indicator a development phase has been undertaken in 2008 and 2009 within the European Topic Center for Water (ETC-W) for EEA. The temperature indicators, developed with the support of MyOcean and Operational Oceanography community, consist of long time series (1870-Today) of SST anomaly able to describe ocean temperature increase due to climate change in the European Seas and on SST trends map of the last 25 years for the European Seas. These last two indicators have been included in the last 2008 EEA report on Impacts of Climate change in the European Seas (http://www.eea.europa.eu/publications/eea_report_2008_4). Moreover MFS re-analysis have been produced for the Mediterranean Sea and it consists of daily output of MFS-OPA hydrodinamic model (1/16 of degree horizontal resolution) that assimilates all available in situ and satellite observation for 1985 to 2007. This reanalysis product is used to detect temperature anomalies over the last 20 years in the coastal zone that could be related with environmental stresses. In addition to that we have also identified a Density indicator that appears relevant for the ecosystem health assessment in the coastal waters.PublishedBerlin, Germany3.7. Dinamica del clima e dell'oceanoope

Marine climate change and environmental indicators from the Marine Core Service

In the framework of the Mediterranean Operational Oceanography Network (MOON, http://www.moon-oceanforecasting.eu) The Mediterranean Forecasting System (Pinardi et al., 2003) has started the design and development of services that include the routine production of environmental and climate indicators. A process of identifying user requirements has been started in collaboration with European Environment Agency and the indicators definition and implementation aim to take user requirements into account. The indicators are extensively used by EEA (EEA web page on indicators: http://themes.eea.europa.eu/indicators/). INGV has carried out an analysis on the possible improvements of existing indicators in use by EEA and on the development of new indicators based on Marine Core Services (MCS) products. The list of indicators includes: Temperature, Chlorophyll-a (from ocean colour), Ocean Currents and Transport, Salinity, Transparency, Sea Level, Sea Ice and Density. A critical analysis has been carried out to identify the relevance of the above-mentioned indicators for EU policies, their spatial and temporal coverage, their accuracy and their availability (Coppini et al., 2008). INGV in collaboration with CNR-ISAC are directly involved on the development of the indicators in the Mediterranean region and European Seas region the Temperature and Chlorophyll-a (Chl-a) products are the most suitable for an indicator development test phase. In particular the OO Chl-a product, deduced from satellite data, is able to contribute to the further development of the EEA Chl-a indicator on eutrohpication that is based on in-situ measurements (CSI023). For this indicator a development phase has been undertaken in 2008 and 2009 within the European Topic Center for Water (ETC-W) for EEA. The temperature indicators, developed with the support of MyOcean and Operational Oceanography community, consist of long time series (1870-Today) of SST anomaly able to describe ocean temperature increase due to climate change in the European Seas and on SST trends map of the last 25 years for the European Seas. These last two indicators have been included in the last 2008 EEA report on Impacts of Climate change in the European Seas (http://www.eea.europa.eu/publications/eea_report_2008_4). Moreover MFS re-analysis have been produced for the Mediterranean Sea and it consists of daily output of MFS-OPA hydrodinamic model (1/16 of degree horizontal resolution) that assimilates all available in situ and satellite observation for 1985 to 2007. This reanalysis product is used to detect temperature anomalies over the last 20 years in the coastal zone that could be related with environmental stresses. In addition to that we have also identified a Density indicator that appears relevant for the ecosystem health assessment in the coastal waters

Impaired Adult Neurogenesis in the Dentate Gyrus of a Triple Transgenic Mouse Model of Alzheimer's Disease

It has become generally accepted that new neurones are added and integrated mainly in two areas of the mammalian CNS, the subventricular zone and the subgranular zone (SGZ) of the dentate gyrus (DG) of the hippocampus, which is of central importance in learning and memory. The newly generated cells display neuronal morphology, are able to generate action potentials and receive functional synaptic inputs, i.e. their properties are similar to those found in mature neurones. Alzheimer's disease (AD) is the primary and widespread cause of dementia and is an age-related, progressive and irreversible neurodegenerative disease that deteriorates cognitive functions. Here, we have used male and female triple transgenic mice (3xTg-AD) harbouring three mutant genes (β-amyloid precursor protein, presenilin-1 and tau) and their respective non-transgenic (non-Tg) controls at 2, 3, 4, 6, 9 and 12 months of age to establish the link between AD and neurogenesis. Using immunohistochemistry we determined the area density of proliferating cells within the SGZ of the DG, measured by the presence of phosphorylated Histone H3 (HH3), and their possible co-localisation with GFAP to exclude a glial phenotype. Less than 1% of the HH3 labeled cells co-localised with GFAP. Both non-Tg and 3xTg-AD showed an age-dependent decrease in neurogenesis. However, male 3xTg-AD mice demonstrated a further reduction in the production of new neurones from 9 months of age (73% decrease) and a complete depletion at 12 months, when compared to controls. In addition, female 3xTg-AD mice showed an earlier but equivalent decrease in neurogenesis at 4 months (reduction of 63%) with an almost inexistent rate at 12 months (88% decrease) compared to controls. This reduction in neurogenesis was directly associated with the presence of β-amyloid plaques and an increase in the number of β-amyloid containing neurones in the hippocampus; which in the case of 3xgTg females was directly correlated. These results suggest that 3xTg-AD mice have an impaired ability to generate new neurones in the DG of the hippocampus, the severity of which increases with age and might be directly associated with the known cognitive impairment observed from 6 months of age onwards . The earlier reduction of neurogenesis in females, from 4 months, is in agreement with the higher prevalence of AD in women than in men. Thus it is conceivable to speculate that a recovery in neurogenesis rates in AD could help to rescue cognitive impairment

The Collagen Chaperone HSP47 Is a New Interactor of APP that Affects the Levels of Extracellular Beta-Amyloid Peptides

Alzheimer disease (AD) is a neurodegenerative disorder characterized by progressive decline of cognitive function that represents one of the most dramatic medical challenges for the aging population. Aβ peptides, generated by processing of the Amyloid Precursor Protein (APP), are thought to play a central role in the pathogenesis of AD. However, the network of physical and functional interactions that may affect their production and deposition is still poorly understood. The use of a bioinformatic approach based on human/mouse conserved coexpression allowed us to identify a group of genes that display an expression profile strongly correlated with APP. Among the most prominent candidates, we investigated whether the collagen chaperone HSP47 could be functionally correlated with APP. We found that HSP47 accumulates in amyloid deposits of two different mouse models and of some AD patients, is capable to physically interact with APP and can be relocalized by APP overexpression. Notably, we found that it is possible to reduce the levels of secreted Aβ peptides by reducing the expression of HSP47 or by interfering with its activity via chemical inhibitors. Our data unveil HSP47 as a new functional interactor of APP and imply it as a potential target for preventing the formation and/or growth amyloid plaques

La malnutrizione nell'anziano fragile: revisione della letteratura ed analisi di linee guida EBM per la definizione di un progetto di miglioramento della qualita presso un I.P.A.B. della Regione Veneto

L'anziano istituzionalizzato per la sua condizione di fragilita , puo andare incontro ad un peggioramento dello stato nutrizionale. Le strutture residenziali hanno un ruolo importante nella presa in carico dei problemi assistenziali promuovendo e favorendo un processo di miglioramento continuo della qualita , attraverso l'utilizzo appropriato di strumenti di management e l'adozione di prassi basate sull'evidenza scientifica

Autophagic/lysosomal dysfunction in Alzheimer's disease

Autophagy serves as the sole catabolic mechanism for degrading organelles and protein aggregates. Increasing evidence implicates autophagic dysfunction in Alzheimer's disease (AD) and other neurodegenerative diseases associated with protein misprocessing and accumulation. Under physiologic conditions, the autophagic/lysosomal system efficiently recycles organelles and substrate proteins. However, reduced autophagy function leads to the accumulation of proteins and autophagic and lysosomal vesicles. These vesicles contain toxic lysosomal hydrolases as well as the proper cellular machinery to generate amyloid-beta, the major component of AD plaques. Here, we provide an overview of current research focused on the relevance of autophagic/lysosomal dysfunction in AD pathogenesis as well as potential therapeutic targets aimed at restoring autophagic/lysosomal pathway function.This item is part of the UA Faculty Publications collection. For more information this item or other items in the UA Campus Repository, contact the University of Arizona Libraries at [email protected]

Methylene blue reduces aβ levels and rescues early cognitive deficit by increasing proteasome activity

Promising results have emerged from a phase II clinical trial testing methylene blue (MB) as a potential therapeutic for Alzheimer disease (AD), where improvements in cognitive functions of AD patients after 6 months of MB administration have been reported. Despite these reports, no preclinical testing of MB in mammals has been published, and thus its mechanism of action in relation to AD pathology remains unknown. In order to elucidate the effects of MB on AD pathology and to determine its mechanism of action, we used a mouse model (3xTg-AD) that develops age-dependent accumulation of Aβ and tau and cognitive decline. Here, we report that chronic dietary MB treatment reduces Aβ levels and improves learning and memory deficits in the 3xTg-AD mice. The mechanisms underlying the effects of MB on Aβ pathology appears to be mediated by an increase in Aβ clearance as we show that MB increases the chymotrypsin- and trypsin-like activities of the proteasome in the brain. To our knowledge, this is the first report showing that MB increases proteasome function and ameliorates AD-like pathology in vivo. Overall, the data presented here support the use of MB for the treatment of AD and offer a possible mechanism of action

Lithium Reduces Tau Phosphorylation but Not Aβ or Working Memory Deficits in a Transgenic Model with Both Plaques and Tangles

Glycogen synthase kinase 3 (GSK-3) is a major kinase implicated in the pathogenesis of Alzheimer’s disease (AD), and reducing its activity may have therapeutic efficacy. Two variants exist, referred to as GSK-3α and GSK-3β. In addition to the latter’s well-described role in the phosphorylation of tau, reports also suggest that GSK-3α may regulate amyloid precursor protein processing and Aβ formation. The activities of both GSK-3α and GSK-3β are reduced by lithium, a well-tolerated drug used in humans to combat bipolar disorder. Here, we investigate the therapeutic efficacy of chronic lithium administration in aged 3xTg-AD mice that harbor both plaques and tangles. We found that lithium reduced tau phosphorylation but did not significantly alter the Aβ load. Despite the reduction in phosphotau, lithium treatment did not improve deficits in working memory. Although other studies have investigated the effects of lithium on tau biochemistry, this study represents the first to address comprehensively its therapeutic potential on other critical aspects of AD including its effect on Aβ and learning and memory. It remains to be determined from human clinical trials whether lithium treatment alone will improve the clinical outcome in AD patients. These results, however, suggest that the most efficacious treatment will be combining lithium with other anti-Aβ interventions

Inducing autophagy by rapamycin before, but not after, the formation of plaques and tangles ameliorates cognitive deficits.

Previous studies have shown that inducing autophagy ameliorates early cognitive deficits associated with the build-up of soluble amyloid-β (Aβ). However, the effects of inducing autophagy on plaques and tangles are yet to be determined. While soluble Aβ and tau represent toxic species in Alzheimer's disease (AD) pathogenesis, there is well documented evidence that plaques and tangles also are detrimental to normal brain function. Thus, it is critical to assess the effects of inducing autophagy in an animal model with established plaques and tangles. Here we show that rapamycin, when given prophylactically to 2-month-old 3xTg-AD mice throughout their life, induces autophagy and significantly reduces plaques, tangles and cognitive deficits. In contrast, inducing autophagy in 15-month-old 3xTg-AD mice, which have established plaques and tangles, has no effects on AD-like pathology and cognitive deficits. In conclusion, we show that autophagy induction via rapamycin may represent a valid therapeutic strategy in AD when administered early in the disease progression