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.
    Neural Regeneration Research 09/2014; 9(1):92-100. DOI:10.4103/1673-5374.125335 · 0.22 Impact Factor
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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.
    Frontiers in Physiology 06/2011; 2:23. DOI:10.3389/fphys.2011.00023 · 3.53 Impact Factor
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    • "The relevance of membrane cholesterol in neurodegenerative processes is demonstrated by the number of research papers devoted to this issue: a PubMed search with 'cholesterol' and 'neurodegenerative diseases' scores more than 1500 entries, 675 of which were released in the last 5 years. Not surprisingly, the topic of cholesterol involvement in the pathogenesis of neurodegenerative diseases has been recently covered by several comprehensive review papers (Adibhatla and Hatcher, 2008; Schweitzer et al., 2009; Liu et al., 2010; Martin et al., 2010; Schengrund, 2010; Zuccato et al., 2010). Besides the effect on membrane properties outlined earlier, it is known that cholesterol in LRs modulates the binding and oligomerization of 'amyloidogenic proteins': these are a series of brain proteins with exceptional conformational plasticity and a high propensity for self-aggregation (Fantini and Yahi, 2010). "
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    ABSTRACT: Type-1 cannabinoid receptor (CB(1)) is the most abundant G-protein-coupled receptor (GPCR) in the brain. CB(1) and its endogenous agonists, the so-called 'endocannabinoids (eCBs)', belong to an ancient neurosignalling system that plays important functions in neurodegenerative and neuroinflammatory disorders like Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis. For this reason, research on the therapeutic potential of drugs modulating the endogenous tone of eCBs is very intense. Several GPCRs reside within subdomains of the plasma membranes that contain high concentrations of cholesterol: the lipid rafts. Here, the hypothesis that changes in membrane fluidity alter function of the endocannabinoid system, as well as progression of particular neurodegenerative diseases, is described. To this end, the impact of membrane cholesterol on membrane properties and hence on neurodegenerative diseases, as well as on CB(1) signalling in vitro and on CB(1) -dependent neurotransmission within the striatum, is discussed. Overall, present evidence points to the membrane environment as a critical regulator of signal transduction triggered by CB(1) , and calls for further studies aimed at better clarifying the contribution of membrane lipids to eCBs signalling. The results of these investigations might be exploited also for the development of novel therapeutics able to combat disorders associated with abnormal activity of CB(1).
    British Journal of Pharmacology 02/2011; 163(7):1379-90. DOI:10.1111/j.1476-5381.2011.01277.x · 4.84 Impact Factor
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