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      Lipid Rafts and Alzheimer’s Disease: Protein-Lipid Interactions and Perturbation of Signaling


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          Lipid rafts are membrane domains, more ordered than the bulk membrane and enriched in cholesterol and sphingolipids. They represent a platform for protein-lipid and protein–protein interactions and for cellular signaling events. In addition to their normal functions, including membrane trafficking, ligand binding (including viruses), axonal development and maintenance of synaptic integrity, rafts have also been implicated in the pathogenesis of several neurodegenerative diseases including Alzheimer’s disease (AD). Lipid rafts promote interaction of the amyloid precursor protein (APP) with the secretase (BACE-1) responsible for generation of the amyloid β peptide, Aβ. Rafts also regulate cholinergic signaling as well as acetylcholinesterase and Aβ interaction. In addition, such major lipid raft components as cholesterol and GM1 ganglioside have been directly implicated in pathogenesis of the disease. Perturbation of lipid raft integrity can also affect various signaling pathways leading to cellular death and AD. In this review, we discuss modulation of APP cleavage by lipid rafts and their components, while also looking at more recent findings on the role of lipid rafts in signaling events.

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          Inflammation and Alzheimer's disease.

          Inflammation clearly occurs in pathologically vulnerable regions of the Alzheimer's disease (AD) brain, and it does so with the full complexity of local peripheral inflammatory responses. In the periphery, degenerating tissue and the deposition of highly insoluble abnormal materials are classical stimulants of inflammation. Likewise, in the AD brain damaged neurons and neurites and highly insoluble amyloid beta peptide deposits and neurofibrillary tangles provide obvious stimuli for inflammation. Because these stimuli are discrete, microlocalized, and present from early preclinical to terminal stages of AD, local upregulation of complement, cytokines, acute phase reactants, and other inflammatory mediators is also discrete, microlocalized, and chronic. Cumulated over many years, direct and bystander damage from AD inflammatory mechanisms is likely to significantly exacerbate the very pathogenic processes that gave rise to it. Thus, animal models and clinical studies, although still in their infancy, strongly suggest that AD inflammation significantly contributes to AD pathogenesis. By better understanding AD inflammatory and immunoregulatory processes, it should be possible to develop anti-inflammatory approaches that may not cure AD but will likely help slow the progression or delay the onset of this devastating disorder.
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            Mammalian nicotinic acetylcholine receptors: from structure to function.

            The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a "receptive substance," from which the idea of a "receptor" came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of alpha-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.
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              The multiple faces of caveolae.

              Caveolae are a highly abundant but enigmatic feature of mammalian cells. They form remarkably stable membrane domains at the plasma membrane but can also function as carriers in the exocytic and endocytic pathways. The apparently diverse functions of caveolae, including mechanosensing and lipid regulation, might be linked to their ability to respond to plasma membrane changes, a property that is dependent on their specialized lipid composition and biophysical properties.

                Author and article information

                Front Physiol
                Front Physiol
                Front. Physio.
                Frontiers in Physiology
                Frontiers Research Foundation
                13 April 2012
                22 June 2012
                : 3
                : 189
                [1] 1simpleSchool of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds Leeds, UK
                [2] 2simpleI.M. Sechenov Institute of Evolutionary Physiology and Biochemistry RAS St. Petersburg, Russia
                Author notes

                Edited by: Alessandro Prinetti, University of Milano, Italy

                Reviewed by: Marco Parenti, University of Milano-Bicocca, Italy; Amitabha Chattopadhyay, Centre for Cellular and Molecular Biology, India

                *Correspondence: Anthony J. Turner, School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, UK e-mail: a.j.turner@ 123456leeds.ac.uk

                This article was submitted to Frontiers in Membrane Physiology and Biophysics, a specialty of Frontiers in Physiology.

                Copyright © 2012 Hicks, Nalivaeva and Turner.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                : 29 March 2012
                : 21 May 2012
                Page count
                Figures: 2, Tables: 0, Equations: 0, References: 260, Pages: 18, Words: 18444
                Review Article

                Anatomy & Physiology
                app,ache,amyloid β peptide,aicd,bace-1,alzheimer’s disease,neprilysin,cholesterol
                Anatomy & Physiology
                app, ache, amyloid β peptide, aicd, bace-1, alzheimer’s disease, neprilysin, cholesterol


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