Erratum: Linking lipids to Alzheimer's disease: cholesterol and beyond
01 Aug 2011-Nature Reviews Neuroscience (Springer Science and Business Media LLC)-Vol. 12, Iss: 8, pp 484-484
TL;DR: This paper presents a new probabilistic procedure called “spot-spot analysis” that quantifies the importance of knowing the carrier and removal status of canine coronavirus as a source of infection for mice.
Abstract: Nature Reviews Neuroscience 12, 284–296 (2011) On page 284 of this article, in the author addresses section, the e-mail address for Gilbert Di Paolo was incorrect. The correct e-mail address is: gil.dipaolo@columbia.edu
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TL;DR: Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders, including Alzheimer's disease and major depression.
Abstract: The brain is highly enriched with fatty acids. These include the polyunsaturated fatty acids (PUFAs) arachidonic acid and docosahexaenoic acid, which are largely esterified to the phospholipid cell membrane. Once PUFAs are released from the membrane, they can participate in signal transduction, either directly or after enzymatic conversion to a variety of bioactive derivatives ('mediators'). PUFAs and their mediators regulate several processes within the brain, such as neurotransmission, cell survival and neuroinflammation, and thereby mood and cognition. PUFA levels and the signalling pathways that they regulate are altered in various neurological disorders, including Alzheimer's disease and major depression. Diet and drugs targeting PUFAs may lead to novel therapeutic approaches for the prevention and treatment of brain disorders.
983 citations
TL;DR: The known genetics of early- and late-onset Alzheimer's disease are reviewed, including APOE, which is a complex disorder with environmental and genetic components leading to disease.
Abstract: Alzheimer's disease is the most common form of dementia and is the only top 10 cause of death in the United States that lacks disease-altering treatments. It is a complex disorder with environmental and genetic components. There are two major types of Alzheimer's disease, early onset and the more common late onset. The genetics of early-onset Alzheimer's disease are largely understood with variants in three different genes leading to disease. In contrast, while several common alleles associated with late-onset Alzheimer's disease, including APOE, have been identified using association studies, the genetics of late-onset Alzheimer's disease are not fully understood. Here we review the known genetics of early- and late-onset Alzheimer's disease.
470 citations
TL;DR: TREM2 is demonstrated as a microglial Aβ receptor transducing physiological and AD-related pathological effects associated with Aβ, and TREM2 interaction with its signaling adaptor DAP12 is enhanced by A β, regulating downstream phosphorylation of SYK and GSK3β.
419 citations
TL;DR: This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms and show how cholesterol metabolism and its complex homeostasis regulation are currently poorly understood.
Abstract: Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer’s disease (AD), Huntington’s disease (HD), Parkinson’s disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.
414 citations
Cites background from "Erratum: Linking lipids to Alzheime..."
...Defects in cholesterol metabolism lead to structural and functional central nervous system (CNS) diseases such as Niemann-Pick C disease, Huntington’s disease, Alzheimer’s disease and Parkinson’s disease (Madra and Sturley, 2010; Block et al., 2010; Di Paolo and Kim, 2011; Wang et al., 2011)....
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...Defects of cholesterol homeostasis in the adult brain are linked to neurodegenerative diseases like Niemann-Pick type C disease or Alzheimer’s disease (Madra and Sturley, 2010; Block et al., 2010; Di Paolo and Kim, 2011; Wang et al., 2011)....
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Duke University1, Indiana University2, Erasmus University Rotterdam3, University of Hawaii4, Shanghai Jiao Tong University5, Durham University6, University of Texas Health Science Center at San Antonio7, University of Arkansas for Medical Sciences8, Houston Methodist Hospital9, Biocrates Life Sciences AG10, University of Pennsylvania11, North Carolina State University12, Leiden University13, Rush University Medical Center14, Columbia University15, University of California, San Francisco16
TL;DR: This data indicates that BAs, products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria and seem dysregulated in Alzheimer's disease (AD).
Abstract: Introduction Increasing evidence suggests a role for the gut microbiome in central nervous system disorders and a specific role for the gut-brain axis in neurodegeneration. Bile acids (BAs), products of cholesterol metabolism and clearance, are produced in the liver and are further metabolized by gut bacteria. They have major regulatory and signaling functions and seem dysregulated in Alzheimer's disease (AD). Methods Serum levels of 15 primary and secondary BAs and their conjugated forms were measured in 1464 subjects including 370 cognitively normal older adults, 284 with early mild cognitive impairment, 505 with late mild cognitive impairment, and 305 AD cases enrolled in the AD Neuroimaging Initiative. We assessed associations of BA profiles including selected ratios with diagnosis, cognition, and AD-related genetic variants, adjusting for confounders and multiple testing. Results In AD compared to cognitively normal older adults, we observed significantly lower serum concentrations of a primary BA (cholic acid [CA]) and increased levels of the bacterially produced, secondary BA, deoxycholic acid, and its glycine and taurine conjugated forms. An increased ratio of deoxycholic acid:CA, which reflects 7α-dehydroxylation of CA by gut bacteria, strongly associated with cognitive decline, a finding replicated in serum and brain samples in the Rush Religious Orders and Memory and Aging Project. Several genetic variants in immune response–related genes implicated in AD showed associations with BA profiles. Discussion We report for the first time an association between altered BA profile, genetic variants implicated in AD, and cognitive changes in disease using a large multicenter study. These findings warrant further investigation of gut dysbiosis and possible role of gut-liver-brain axis in the pathogenesis of AD.
322 citations
Cites background from "Erratum: Linking lipids to Alzheime..."
...Cholesterol metabolism in the liver is thought to play a key role in AD[18]....
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References
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TL;DR: Exploration of lipid dysregulation in AD and identification of novel therapeutic agents acting through relevant lipid pathways offers new and effective options for the treatment of this devastating disorder.
Abstract: Lipid-mediated signalling regulates a plethora of physiological processes, including crucial aspects of brain function. In addition, dysregulation of lipid pathways has been implicated in a growing number of neurodegenerative disorders, such as Alzheimer's disease (AD). Although much attention has been given to the link between cholesterol and AD pathogenesis, growing evidence suggests that other lipids, such as phosphoinositides and phosphatidic acid, have an important role. Regulators of lipid metabolism (for example, statins) are a highly successful class of marketed drugs, and exploration of lipid dysregulation in AD and identification of novel therapeutic agents acting through relevant lipid pathways offers new and effective options for the treatment of this devastating disorder.
758 citations