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Arc - a new covenant for Alzheimer's disease?

A recent human genetic study (Landgren et al., 2012) has shown that a particular sequence variant in the 3'UTR of Arc (activity-regulated cytoskeleton-associated protein) mRNA leads to a decreased likelihood of developing Alzheimer's disease. This gives genetic reality to a series of biochemical observations in cells and mouse models that suggest Arc expression affects AΒ42 levels and thus pathology in Alzheimer's disease.

Arc is a neuronal protein that is only found in the postsynaptic component of the synapse (Chowdhury et al., 2006). It interacts with endophilin and dynamin in an endocytic pathway. It is well known as an "immediate early gene" in protein-dependent memory and plasticity, and for its role in the trafficking of AMPA receptors. Arc expression is increased by persistent neuronal activity in the visual cortex or in cultured neurons (Shepherd et al., 2006; Gao et al., 2010), and acts to increase the rate of endocytosis of AMPA receptors, resulting in homeostatic downregulation of synaptic strength.

A recent study by Wu et al. (2011) provides a biochemical rationale for a link between Arc activity and Alzheimer's disease. There is evidence that processing of APP, which produces AΒ42, occurs primarily in sorting/early endosomes, and blocking endocytosis reduces overall AΒ42 levels and blocks activity-dependent AΒ42 increases. This study shows that Arc interacts directly with the N-terminus of PS1/y-secretase and colocalises with PS1 in dendrites in association with endosome membranes. Blocking this interaction prevents activity dependent increases in AΒ42 production. Arc also colocalises with APP and Rab11 at endosomes, and AΒ42 levels and plaque load are reduced in Arc-/- AD model mice (APPSWE;PS1ΔE9). This has suggested a model in which Arc increases the association of y-secretase with endosomes that contain APP, leading to enhanced y-secretase cleavage of APP and more AΒ42. Arc is thus a key mediator of activity-dependent AΒ42 production and its contribution to Alzheimer's disease pathology. The observed human 3'UTR variant may modulate the localisation of Arc, slightly altering the activity-dependent response.

ARC is just one of the human proteins that Brainwave-Discovery Ltd. is expressing in Drosophila synapses. We can help you discover the in vivo effects of your compounds on interactions of Arc with its partners, within a normal or an Alzheimer's disease background. We also link in to a Europe-wide synaptic analysis network, SynSys). For more information check out our website or contact info@brainwave-discovery.com

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