Cholesterol cures Alzheimer's
Citation: Abad-Rodriguez J, Ledesma MD, Craessaerts K, Perga S, Medina M, Delacourte A, Dingwall C, De Strooper B, Dotti CG. Neuronal membrane cholesterol loss enhances amyloid peptide generation. J Cell Biology Vol.167(5), 953-960 (6 December 2004) [Further details]
Abstract: Recent experimental and clinical retrospective studies support the view that reduction of brain cholesterol protects against Alzheimer's disease (AD). However, genetic and pharmacological evidence indicates that low brain cholesterol leads to neurodegeneration. This apparent contradiction prompted us to analyze the role of neuronal cholesterol in amyloid peptide generation in experimental systems that closely resemble physiological and pathological situations. We show that, in the hippocampus of control human and transgenic mice, only a small pool of endogenous APP and its beta-secretase, BACE 1, are found in the same membrane environment. Much higher levels of BACE 1-APP colocalization is found in hippocampal membranes from AD patients or in rodent hippocampal neurons with a moderate reduction of membrane cholesterol. Their increased colocalization is associated with elevated production of amyloid peptide. These results suggest that loss of neuronal membrane cholesterol contributes to excessive amyloidogenesis in AD and pave the way for the identification of the cause of cholesterol loss and for the development of specific therapeutic strategies.
Authors: Jose Abad-Rodriguez, Maria Dolores Ledesma, Katleen Craessaerts, Simona Perga, Miguel Medina, Andre Delacourte, Colin Dingwall, Bart De Strooper, and Carlos G. Dotti
Authors Institution: Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, 10043 Orbassano (TO), Italy; Center for Human Genetics, Catholic University of Leuven and Flanders Interuniversitary Institute for Biotechnology, 3000 Leuven, Belgium; Unité INSERM 422, Lille, France; Neurology and GI CEDD, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM195AW, England, UK
Key words: Alzheimer's disease; cholesterol; lipids; synaptic function; neuron; neural plasticity; neurodegeneration; memory loss; amyloid; secretases;
Key note by Jose Abad-Rodriguez and Maria-Dolores Ledesma: "We here provide evidence that cholesterol-rich membrane domains (rafts) act as "basins" to segregate the APP-b-secretase BACE from its substrate APP. A mild but significant reduction of membrane cholesterol observed in Alzheimer's disease patient brains or induced in cultured neurons, leads to raft disorganization. Such an alteration results in increased amyloid production. These data suggest that approaches aimed to prevent neuronal cholesterol loss, contrarily to what has been proposed, should be taken into account when considering AD treatments."
Further reading: see related articles at Neurobiology of Lipids.
Abstract: Recent experimental and clinical retrospective studies support the view that reduction of brain cholesterol protects against Alzheimer's disease (AD). However, genetic and pharmacological evidence indicates that low brain cholesterol leads to neurodegeneration. This apparent contradiction prompted us to analyze the role of neuronal cholesterol in amyloid peptide generation in experimental systems that closely resemble physiological and pathological situations. We show that, in the hippocampus of control human and transgenic mice, only a small pool of endogenous APP and its beta-secretase, BACE 1, are found in the same membrane environment. Much higher levels of BACE 1-APP colocalization is found in hippocampal membranes from AD patients or in rodent hippocampal neurons with a moderate reduction of membrane cholesterol. Their increased colocalization is associated with elevated production of amyloid peptide. These results suggest that loss of neuronal membrane cholesterol contributes to excessive amyloidogenesis in AD and pave the way for the identification of the cause of cholesterol loss and for the development of specific therapeutic strategies.
Authors: Jose Abad-Rodriguez, Maria Dolores Ledesma, Katleen Craessaerts, Simona Perga, Miguel Medina, Andre Delacourte, Colin Dingwall, Bart De Strooper, and Carlos G. Dotti
Authors Institution: Cavalieri Ottolenghi Scientific Institute, Universita degli Studi di Torino, 10043 Orbassano (TO), Italy; Center for Human Genetics, Catholic University of Leuven and Flanders Interuniversitary Institute for Biotechnology, 3000 Leuven, Belgium; Unité INSERM 422, Lille, France; Neurology and GI CEDD, GlaxoSmithKline Pharmaceuticals, Harlow, Essex CM195AW, England, UK
Key words: Alzheimer's disease; cholesterol; lipids; synaptic function; neuron; neural plasticity; neurodegeneration; memory loss; amyloid; secretases;
Key note by Jose Abad-Rodriguez and Maria-Dolores Ledesma: "We here provide evidence that cholesterol-rich membrane domains (rafts) act as "basins" to segregate the APP-b-secretase BACE from its substrate APP. A mild but significant reduction of membrane cholesterol observed in Alzheimer's disease patient brains or induced in cultured neurons, leads to raft disorganization. Such an alteration results in increased amyloid production. These data suggest that approaches aimed to prevent neuronal cholesterol loss, contrarily to what has been proposed, should be taken into account when considering AD treatments."
Further reading: see related articles at Neurobiology of Lipids.
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