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Cofilin-1 activity is modulated by age, Alzheimer's disease pathology and gamma secretase

Barone, Eugenio and Mosser, Sebastien and Frearing, Patrick C (2014) Cofilin-1 activity is modulated by age, Alzheimer's disease pathology and gamma secretase. Biochim Biophys Acta, 1842 (12 Pt ). pp. 2500-2509.

Abstract

Rapid remodeling of the actin cytoskeleton in the pre and/or post-synaptic compartment is responsible for the regulation of neuronal plasticity, which is an important process for learning and memory. Cofilin1 is an essential actin binding protein, which regulates actin dynamics by enhancing the turnover of actin filaments. Through its activity, Cofinlin1 reulates neuronal outgrowth, endocytosis, receptor recycling, regulation of ion channels and ATP-energy management. Cognitive decline associated witha Cofilin1 activity dysregulation-dependnet impairment of the above mentioned processes has been observed both during normal aging and Alzheimer Disease (AD). Gamma Secretase is directly implicated in the progression of AD, and notably, an age-associated modification of its activity was recently demonstrated, linking neuronal aging to sporadic AD. Here we report a decrease of Cofilin1 protein levels, associated with an increase of Cofilin1 phosphorylation/inactiviation with age and AD both in vivo and in vitro. Interestingly, chemical or genetic inhibitions of gamma secretase prevented the observed inactivation, highlighting Cofilin1 as a new downstream target of this protease. These results are profoundly important in understandiong the molecular mechanisms leading to impaired synaptic plasticity, both during aging and AD. They further have the potential to impact the development of theraies to safely treat AD.

Item Type: Article
Keywords: Alzheimer's disease, aging, cofilin1, gamma secretase
Date Deposited: 15 Oct 2015 23:45
Last Modified: 15 Oct 2015 23:45
URI: https://oak.novartis.com/id/eprint/20405

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