An Amyloid-Notch Hypothesis for Alzheimer’s Disease

An Amyloid-Notch Hypothesis for Alzheimer’s Disease

Douglas W. Ethell

The Neuroscientist 2010, First published on June 30, doi:10.1177/1073858410366162

pas d’accès à la revue, donc pas lu le papier, mais l’abstract est séduisant et colle avec le modèle sur lequel on travaille, plus si Ethell a la gentillesse de m’envoyer une copie. Exactement ce à quoi je pensais en lisant l’abstract, excellent !

For more than 20 years, the amyloid hypothesis has provided an important framework for Alzheimer’s disease (AD) research, yet after 50,000 papers, the nonpathological function of beta-amyloid (Aß) remains enigmatic. This mystery is compounded by an absence of gross abnormalities in amyloid precursor protein (APP)–deficient mice and zebrafish even though APP has been highly conserved throughout vertebrate evolution. Here, the author hypothesizes that vertebrate cells express APP and release A as part of a mechanism to optimize blood vessel density with the metabolite removal needs of local tissue neighborhoods. High-gain feedback of Aß production at the rate-limiting γ-secretase step reduces Aß production and Notch activation. Notch inhibition causes endothelial cells to adopt a tip cell morphology that induces more highly branched blood vessels. In vivo, γ-secretase inhibitors block Notch signaling and induce dense capillary networks that are similar to those in the brains of AD patients and mice. Notch inhibition could also contribute to synapse loss by reducing EphB2 receptor expression. EphB receptors are critical for the maintenance of dendritic spine morphology, and deficiencies result in immature spines that lack synaptic activity. This revised amyloid-Notch hypothesis may also explain the disappointing results of recent clinical trials with γ-secretase inhibitors.

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  1. #1 par den le décembre 26, 2010 - 4:07

    in layman’s terms please ?

  2. #2 par Oldcola le décembre 26, 2010 - 4:50

    Hi Den,
    I’ll try to keep it simple and if you want more details I’ll be happy to go in that.

    Douglas’s hypothesis is that the amyloid hypothesis is not « all of it » when it comes to explain AD and it need to be completed. He introduce an extension taking in account vascular alterations observed in AD brains wich may be the consequences of Notch inhibition, and offer a way to test his extension in APP-deficient mice (and zebrafish).

    I love his approach because it completes one of my models of another neurodegenerative disease, multiple sclerosis, with a strong inflammatory component which may be understood via a deregulation of Notch signaling.

    For the moment I’m struggling to find where (and why) Douglas’ and my hypotheses could be wrong and design a set of experiments to test them at least in vitro or in one of the multiple sclerosis animal models. We have some (very) indirect evidence that the path is worth following and it could benefit any pathology with a neuroinflammatory component.

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