APP role in Alzheimer's disease

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The amyloid precursor protein (APP) plays a central role in Alzheimer's disease, but its actions in normal development are not well understood. Here, a tagged APP ectodomain was used to identify extracellular binding partners in developing chick brain. Prominent binding sites were seen in the olfactory bulb and on retinal axons growing into the optic tectum. Co-precipitation from these tissues and tandem mass spectrometry led to the identification of two associated proteins: contactin 4 and NgCAM. In vitro binding studies revealed direct interactions among multiple members of the APP and contactin protein families. Levels of the APP processing fragment, CTF, were modulated by both contactin 4 and NgCAM. In the developing retinotectal system, APP, contactin 4 and NgCAM are expressed in the retina and tectum in suitable locations to interact. Functional assays revealed regulatory effects of both APP and contactin 4 on NgCAM-dependent growth of cultured retinal axons, demonstrating specific functional interactions among these proteins. These studies identify novel binding and functional interactions among proteins of the APP, contactin and L1CAM families, with general implications for mechanisms of APP action in neural development and disease. (L1CAM family proteins are transmembrane proteins and are members of the IgCAM (immunoglobulin-related cell adhesion molecule. L1CAM and its chicken homolog NgCAM have been widely studied for functions in axon growth, guidance and fasciculation.)

Amyloid precursor protein (APP) is a transmembrane protein that plays a key role in Alzheimer's disease. This disease is characterized by intraneuronal tangles and extracellular plaques, and the amyloid beta-peptide (Aβ), which is derived from APP upon cleavage by β- and -secretases, is the major component of the plaques. Mutations in APP have been linked to familial Alzheimer's disease, and the most widely accepted models of disease etiology propose that Aβ aggregates or oligomers trigger a cascade of events causing damage to neuronal connections and cell death ...Development. 2008 Mar;135(6):1189

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