STRESSAMYLOIDCASCADE

Stress cascades and Alzheimer's disease

 Coordinatore  

 Organization address address: Hofgartenstrasse 8
city: MUENCHEN
postcode: 80539

contact info
Nome: Silvia
Cognome: Juckoff
Email: send email
Telefono: +49 89 30622474
Fax: +49 89 30622444

 Nazionalità Coordinatore Non specificata
 Totale costo 169˙863 €
 EC contributo 169˙863 €
 Programma FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
 Code Call FP7-PE
 Anno di inizio 2012
 Periodo (anno-mese-giorno) 2012-10-01   -   2014-09-30

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    MAX PLANCK GESELLSCHAFT ZUR FOERDERUNG DER WISSENSCHAFTEN E.V.

 Organization address address: Hofgartenstrasse 8
city: MUENCHEN
postcode: 80539

contact info
Nome: Silvia
Cognome: Juckoff
Email: send email
Telefono: +49 89 30622474
Fax: +49 89 30622444

DE (MUENCHEN) coordinator 169˙863.20

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

dhf    cognitive    expression    model    stressamyloidcascade    risk    neurotrophic    abeta    mice    asymptomatic    decline    stress    ad    treat    alzheimer    skills    patients    cellular    molecular    prevent    later    oral    recent    app    host    depression    disease    implicated    deficits    neuronal    beta    team    brain    spatio    suggests    reverse    amyloid    animal    evidence    memory    tested    scientists    amyloidogenic    progression    temporal    levels    fact    impairments    age    treatment    gc    ribotag    arcabeta   

 Obiettivo del progetto (Objective)

'Global increases in lifespan make the challenge to prevent and treat Alzheimer’s disease (AD) urgent. While the etiology of non-familial/sporadic AD is largely unknown, many AD patients have elevated stress hormone (glucocorticoid, GC) levels and recent animal studies show that high GC levels promote production of amyloidogenic peptides (key pathogenic players in AD) in association with memory deficits. Stress/GC are implicated in mood and cognitive disorders, and meta-analyses identify depression (often associated with cognitive deficits) as a risk for AD. This, and the fact that depression and AD involve similar limbic-cortical substrates, suggests shared spatio-temporal trajectories, with the two conditions representing early and late manifestations of increased amyloid beta (A-beta) levels. This proposal aims to i) define the spatio-temporal progression of the impact of stress on A-beta production based on morphochemical (immunochemical, gene expression, morphometric) mapping; and ii) identify the cellular targets and molecular mechanisms through which stress is pro-amyloidogenic (multiplex qPCR, Western blot, enzymatic activity assay). Two transgenic mice (arcAbeta and RiboTag mice) of different ages and sexes (women are more prone to AD and depression) will be used. Analysis of cellular events in genetically-marked (RiboTag) neuronal sub-populations adds innovative value. The applicant will apply his existing skills in structural and behavioral neurobiology, complemented by additional (primary neuronal culture, molecular and cellular neuroanatomy) and state-of-the-art methodologies (high-speed voltage-sensitive dye imaging and optogenetics), acquired at the host institute. Besides offering technical and generic skills, the host institute allows dialogue between basic and clinical researchers.'

Introduzione (Teaser)

Alzheimer's disease (AD) is a progressive, irreversible and devastating disease. New evidence obtained in mice suggests that short-term oral administration of an agonist of the brain-derived neurotrophic factor to asymptomatic at-risk patients might help delay or prevent AD progression.

Descrizione progetto (Article)

AD slowly impairs memory function, thinking skills and eventually the ability to carry out everyday tasks. According to the National Institute of Aging in the United States, current estimates suggest that AD may in fact be the third leading cause of death behind heart disease and cancer, particularly in the elderly. Increasing evidence points to an inter-relationship among chronic stress, depression, cognitive deficits and AD. EU-funded scientists set out to untangle the relationships and search for preventative treatment with work on the STRESSAMYLOIDCASCADE (Stress cascades and Alzheimer's disease) project.

The team focused on recent reports suggesting that neurotrophins can decrease the neuropathological and cognitive consequences of stress in mice. The scientists tested the hypothesis that potentiation of brain neurotrophic activity might prevent or reverse the neurodegenerative and cognitive defects associated with the disease.

ArcAbeta mice serve as an animal model of AD; the mice over-produce the amyloid precursor protein (APP) whose cleavage results in production of the amyloid-beta (Abeta) peptide which is strongly implicated in the pathophysiology of AD. Abeta is the main component of the plaques characteristic of AD. The team used ArcAbeta mice in order to test the effect of a small molecule (7,8-DHF) that mimicks the activity of a brain neurotrophin.

Young mice (asymptomatic) were given oral 7,8-DHF and their cognitive performance was tested 5 months later when untreated ArcAbeta mice showed obvious cognitive decline . Treatment with 7,8-DHF prevented the age-associated impairments in spatial memory. It also reduced the levels of Abeta in AD-relevant brain areas (hippocampus, cortex). Further analysis indicated that the reduction in Abeta levels is related to down-regulation of an enzyme that generates Abeta from APP by 7,8-DHF.

This is the first known demonstration that transient, systemic pharmacological treatment, administered before expression of signs of AD-like features, can prevent and reverse the manifestation of age-associated cognitive impairments in a laboratory model of AD. In addition, later intervention with the test drug 7,8-DHF, after appearance of cognitive decline, reversed the behavioural impairments.

The STRESSAMYLOIDCASCADE project has produced strong evidence that neurotrophic molecules have the potential to prevent and treat AD.

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