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Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice.
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Neuritic plaques are relevant to AD.
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Supporting(11)
Consistent(1)
Description: Neuritic plaques have been considered as a probable cause of neuronal degeneration and death in AD long before the discovery that plaques contain Aβ. Since then, evidence has accumulated indicating that Aβ may be responsible – at least in part – for the pathology and symptoms of AD. It appeared that the oligomerization state of the peptide is highly relevant to Aβ toxicity. Aβ is generated from APP likely as monomer, while mature plaques contain Aβ fibrils, which form as a result of peptide aggregation. Between monomers and fibrils, there are many oligomeric forms – from dimers and trimers to Aβ-derived diffusible ligands (ADDLs), annular assemblies, and protofibrils (the latter forms being mainly the result of in vitro polymerization). Recent work has shown that it is the presence of the soluble Aβ oligomers (dimers, trimers, or higher oligomers, such as Aβ*56) rather than the fibrillar Aβ and the brain plaque load which correlates with the learning and memory deficits, in mouse models of AD. If the fibrillar Aβ present in mature plaques is less toxic than the oligomers, then are the neuritic plaques less relevant to AD pathology than the soluble Aβ oligomers? Not at all! Recent studies suggest that the plaques might function as reservoirs of the highly pathogenic, smaller Aβ oligomers, from which they can be released.
Experimental Approach: Mechanism - biochemistry and structural biology,
Pathogenic Narrative Tags: Pathologic change
Supporting Evidence
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Walsh D,
Klyubin I,
Fadeeva J,
Cullen W,
Anwyl R,
Wolfe M,
Rowan M,
Selkoe D
Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
Nature. 2002 Apr 4;416(6880):535-9 -
Shankar G,
Li S,
Mehta T,
Garcia-Munoz A,
Shepardson N,
Smith I,
Brett F,
Farrell M,
Rowan M,
Lemere C,
Regan C,
Walsh D,
Sabatini B,
Selkoe D
Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
Nature medicine. 2008 Aug;14(8):837-42 -
LaFerla F,
Green K,
Oddo S
Intracellular amyloid-beta in Alzheimer's disease.
Nature reviews. Neuroscience. 2007 Jul;8(7):499-509 -
Glenner G,
Wong C
Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein.
Biochemical and biophysical research communications. 1984 May 16;120(3):885-90 -
Cleary J,
Walsh D,
Hofmeister J,
Shankar G,
Kuskowski M,
Selkoe D,
Ashe K
Natural oligomers of the amyloid-beta protein specifically disrupt cognitive function.
Nature neuroscience. 2005 Jan;8(1):79-84 -
Lesné S,
Koh M,
Kotilinek L,
Kayed R,
Glabe C,
Yang A,
Gallagher M,
Ashe K
A specific amyloid-beta protein assembly in the brain impairs memory.
Nature. 2006 Mar 16;440(7082):352-7 -
Martins I,
Kuperstein I,
Wilkinson H,
Maes E,
Vanbrabant M,
Jonckheere W,
Van Gelder P,
Hartmann D,
D'Hooge R,
De Strooper B,
Schymkowitz J,
Rousseau F
Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice.
The EMBO journal. 2008 Jan 9;27(1):224-33 -
Lambert M,
Barlow A,
Chromy B,
Edwards C,
Freed R,
Liosatos M,
Morgan T,
Rozovsky I,
Trommer B,
Viola K,
Wals P,
Zhang C,
Finch C,
Krafft G,
Klein W
Diffusible, nonfibrillar ligands derived from Abeta1-42 are potent central nervous system neurotoxins.
Proceedings of the National Academy of Sciences of the United States of America. 1998 May 26;95(11):6448-53 -
Kamenetz F,
Tomita T,
Hsieh H,
Seabrook G,
Borchelt D,
Iwatsubo T,
Sisodia S,
Malinow R
APP processing and synaptic function.
Neuron. 2003 Mar 27;37(6):925-37 -
Haass C,
Selkoe D
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
Nature reviews. Molecular cell biology. 2007 Feb;8(2):101-12 -
Masters C,
Simms G,
Weinman N,
Multhaup G,
McDonald B,
Beyreuther K
Amyloid plaque core protein in Alzheimer disease and Down syndrome.
Proceedings of the National Academy of Sciences of the United States of America. 1985 Jun;82(12):4245-9
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The invariant accumulation of insoluble amyloid plaques in AD may signify that they serve as relatively inert reservoirs of small bioactive oligomers, and they may disassemble more readily in the presence of lipids.
Shankar G
Li S
Mehta T
Garcia-Munoz A
Shepardson N
Smith I
Brett F
Farrell M
Rowan M
Lemere C
Regan C
Walsh D
Sabatini B
Selkoe D
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PubMed
The invariant accumulation of insoluble amyloid plaques in AD may signify that they serve as relatively inert reservoirs of small bioactive oligomers, and they may disassemble more readily in the presence of lipids.
SHOW Details
Supporting(2)
Consistent(1)
Genes/Proteins: (1)
Supporting(2)
Consistent(1)
Genes/Proteins: (1)
Description: That plaque cores may release locally active Aβ species in vivo is suggested by a penumbra of synapse loss around cores in APP transgenic mice.
Experimental Approach: Mechanism - biochemistry and structural biology
Pathogenic Narrative Tags: Pathologic change
Supporting Evidence
Genes/ProteinsExperimental Approach: Mechanism - biochemistry and structural biology
Pathogenic Narrative Tags: Pathologic change
Supporting Evidence
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Spires T,
Meyer-Luehmann M,
Stern E,
McLean P,
Skoch J,
Nguyen P,
Bacskai B,
Hyman B
Dendritic spine abnormalities in amyloid precursor protein transgenic mice demonstrated by gene transfer and intravital multiphoton microscopy.
The Journal of neuroscience : the official journal of the Society for Neuroscience. 2005 Aug 3;25(31):7278-87 -
Martins I,
Kuperstein I,
Wilkinson H,
Maes E,
Vanbrabant M,
Jonckheere W,
Van Gelder P,
Hartmann D,
D'Hooge R,
De Strooper B,
Schymkowitz J,
Rousseau F
Lipids revert inert Abeta amyloid fibrils to neurotoxic protofibrils that affect learning in mice.
The EMBO journal. 2008 Jan 9;27(1):224-33
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Neuritic plaques are relevant to AD.
Muresan Z
Muresan V
