Lipid rafts: Keys to neurodegeneration

Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, United States.
Brain research bulletin (Impact Factor: 2.72). 03/2010; 82(1-2):7-17. DOI: 10.1016/j.brainresbull.2010.02.013
Source: PubMed


The increase in life expectancy seen in many countries has been accompanied by an increase in the number of people living with dementia and a growing need for health care. The large number of affected individuals emphasizes the need to identify causes for the phenotypes associated with diseases such as Alzheimer's, Parkinson's, amyotrophic lateral sclerosis, Huntington's, and those caused by prions. This review addresses the hypothesis that changes in lipid rafts induced by alterations in their ganglioside and/or cholesterol content or the interaction of mutant proteins with them provide the keys to understanding the onset of neurodegeneration that can lead to dementia. The biological function(s) of raft-associated gangliosides and cholesterol are discussed prior to reviewing what is known about their roles in lipid rafts in the aforementioned diseases. It concludes with some questions that need to be addressed in order to provide investigators with the basis for identifying small molecule agonists or antagonists to test as potential therapeutics.

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    • "Alterations of lipid rafts may result from complex deregulation of neuronal physiology. Numerous studies have reported the association of lipid rafts with neurodegenerative diseases, particularly Alzheimer's disease[256571727475]. "
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    ABSTRACT: Amyloid-beta peptide is the main component of amyloid plaques, which are found in Alzheimer's disease. The generation and deposition of amyloid-beta is one of the crucial factors for the onset and progression of Alzheimer's disease. Lipid rafts are glycolipid-rich liquid domains of the plasma membrane, where certain types of protein tend to aggregate and intercalate. Lipid rafts are involved in the generation of amyloid-beta oligomers and the formation of amyloid-beta peptides. In this paper, we review the mechanism by which lipid rafts disturb the aberrant degradative autophagic-lysosomal pathway of amyloid-beta, which plays an important role in the pathological process of Alzheimer's disease. Moreover, we describe this mechanism from the view of the Two-system Theory of fasciology and thus, suggest that lipid rafts may be a new target of Alzheimer's disease treatment.
    Full-text · Article · Sep 2014 · Neural Regeneration Research
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    • "During this process, APP is initially cleaved by bsecretase (BACE) followed by the subsequent intramembrane proteolysis of the membrane bound C-terminal fragment catalyzed by g-secretase to generate Ab40 and Ab42 peptides. A great deal of evidence has shown that the amyloidogenic processing of APP occurs primarily in membrane signaling platforms designated as lipid rafts (Cordy et al., 2006; Schengrund, 2010). Lipid rafts are membrane microdomains enriched in cholesterol, glycosphingolipids , and sphingomyelin into which specific subsets of proteins and lipids partition, to build up signaling platforms that are essential for a number of neuronal functions (Rushworth and Hooper, 2011; Tsui-Pierchala et al., 2002). "
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    ABSTRACT: The presence of lipid alterations in lipid rafts from the frontal cortex in late stages of Alzheimer's disease (AD) has been recently demonstrated. Here, we have isolated and analyzed the lipid composition of lipid rafts from different brain areas from control and AD subjects at initial neuropathologic stages. We have observed that frontal cortex lipid rafts are profoundly altered in AD brains from the earliest stages of AD, namely AD I/II. These changes in the lipid matrix of lipid rafts affected both lipid classes and fatty acids and were also detected in the entorhinal cortex, but not in the cerebellum from the same subjects. Paralleling these changes, lipid rafts from AD frontal and entorhinal cortices displayed higher anisotropy for environment-sensitive probes, indicating that lipid changes in AD lipid rafts increased membrane order and viscosity in these domains. The pathophysiological consequences of these alterations in the development and progression of AD were strengthened by the significant, and specific, accumulation of β-secretase within the lipid rafts of AD subjects even at the earliest stages. Our results provide a mechanistic connection between lipid alterations in these microdomains and amyloidogenic processing of amyloid precursor protein.
    Full-text · Article · Feb 2014 · Neurobiology of aging
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    • "Alterations in the physicochemical properties of lipid rafts may also affect structure–activity relationships of proteins involved in a broad range of neurodegenerative diseases, including, apart from AD, prion diseases, Huntington's disease, amyotrophic lateral sclerosis, and Parkinson's disease (Taylor and Hooper, 2007; Schengrund, 2010). Additional support for this concept is starting to be provided by the observed integration in lipid rafts of proteins which are hallmarks of different pathogenesis, such as the prion protein (PrP c ), alpha synuclein and parkin (Park et al., 2009; Pani et al., 2010; Schengrund, 2010). Thus, PrP c is constitutively expressed in neurons as a GPI-anchored protein localized in lipid rafts, and these compartments play an important role in the propagation of prion disease (Russelakis-Caneiro et al., 2004; Morris et al., 2006). "
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    ABSTRACT: Emerging data suggest that compartmentalization of signaling molecules into particular membrane compartments, or lipid rafts, may be at the basis of numerous activities related to neuronal preservation against different pathologies. These signaling platforms (signalosomes) are formed by complex lipid and protein that may interact to develop a plethora of different physiological responses upon activation by different extracellular stimuli, thereby contributing to neuroprotection. One of the first studied signalosomes involved in neuroprotection against Alzheimer's disease (AD) is constituted by estrogen receptor (ER), in association with scaffolding caveolin-1 and a voltage-dependent anion channel (VDAC). In this complex, ER plays a neuroprotective role partially through the modulation of VDAC activation, a porin involved in amyloid-beta-induced toxicity. Interestingly, ER and VDAC interactions appear to be altered in lipid rafts of AD brains, a phenomenon that may contribute to neuronal impairment. Alterations in lipid components of these subdomains may contribute to destabilization of this macrocomplex. These recent advances in the relevance of signaling platforms related to brain preservation, in particular against AD, are discussed in this work.
    Full-text · Article · Jun 2011 · Frontiers in Physiology
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