Alzheimer's disease as homeostatic responses to age-related myelin breakdown
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This work delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides "upstream" treatment targets and reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits as by-products of homeostatic myelin repair processes.Citations
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An automated high-resolution in vivo screen in zebrafish to identify chemical regulators of myelination.
Jason J Early,Katy L. H. Cole,Jill M Williamson,Matthew Swire,Hari Kamadurai,Marc A. T. Muskavitch,David A. Lyons +6 more
TL;DR: This work automates the delivery of zebrafish larvae to a spinning disk confocal microscope and develops an image analysis pipeline that facilitated a screen of compounds with epigenetic and post-translational targets for their effects on regulating myelinating oligodendrocyte number.
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Quantitative MRI provides markers of intra-, inter-regional, and age-related differences in young adult cortical microstructure.
Daniel Carey,Daniel Carey,Francesco Caprini,Micah Allen,Antoine Lutti,Nikolaus Weiskopf,Geraint Rees,Geraint Rees,Martina F. Callaghan,Frederic Dick +9 more
TL;DR: The findings afford an improved understanding of ontogeny in early adulthood and offer normative quantitative MR data for inter‐ and intra‐cortical composition, which may be used as benchmarks in further studies.
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Cognitive reserve, cortical plasticity and resistance to Alzheimer's disease.
TL;DR: Although multiple factors and possible interventions may influence cognitive reserve and susceptibility to dementia, much more work is required on the mechanisms of action in order to determine which, if any, may improve the clinical and epidemiological picture.
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Prevalent iron metabolism gene variants associated with increased brain ferritin iron in healthy older men.
George Bartzokis,George Bartzokis,Po H. Lu,Todd A. Tishler,Todd A. Tishler,Douglas G. Peters,Douglas G. Peters,Anastasia Kosenko,Anastasia Kosenko,Katherine A. Barrall,J. Paul Finn,Pablo Villablanca,Gerhard Laub,Lori L. Altshuler,Lori L. Altshuler,Daniel H. Geschwind,Jim Mintz,Elizabeth B. Neely,James R. Connor +18 more
TL;DR: This work reports the first published evidence that these highly prevalent genetic variants in iron metabolism genes can influence brain iron levels in men, and clarifying mechanisms of brain iron accumulation may help identify novel interventions for age-related neurodegenerative diseases.
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Re-imagining Alzheimer's disease - the diminishing importance of amyloid and a glimpse of what lies ahead.
Kai Hei Tse,Karl Herrup +1 more
TL;DR: This review offers three experimentally verified amyloid‐independent mechanisms, each of which plausibly contributes substantially to the aetiology of Alzheimer's disease: loss of DNA integrity, faulty cell cycle regulation, regression of myelination.
References
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The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics
John Hardy,Dennis J. Selkoe +1 more
TL;DR: It has been more than 10 years since it was first proposed that the neurodegeneration in Alzheimer's disease (AD) may be caused by deposition of amyloid β-peptide in plaques in brain tissue and the rest of the disease process is proposed to result from an imbalance between Aβ production and Aβ clearance.
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Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families
Elizabeth H. Corder,Ann M. Saunders,Warren J. Strittmatter,Donald E. Schmechel,P. C. Gaskell,Gary W. Small,A. D. Roses,Jonathan L. Haines,Margaret A. Pericak-Vance +8 more
TL;DR: The APOE-epsilon 4 allele is associated with the common late onset familial and sporadic forms of Alzheimer9s disease (AD) in 42 families with late onset AD.
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Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment.
Robert D. Terry,Eliezer Masliah,David P. Salmon,Nelson Butters,Richard DeTeresa,Robert Hill,Lawrence A. Hansen,Robert Katzman +7 more
TL;DR: Both linear regressions and multivariate analyses correlating three global neuropsychological tests with a number of structural and neurochemical measurements performed on a prospective series of patients with Alzheimer's disease and 9 neuropathologically normal subjects reveal very powerful correlations with all three psychological assays.
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Alzheimer's Disease Is a Synaptic Failure
TL;DR: Mounting evidence suggests that this syndrome begins with subtle alterations of hippocampal synaptic efficacy prior to frank neuronal degeneration, and that the synaptic dysfunction is caused by diffusible oligomeric assemblies of the amyloid β protein.
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Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory.
Ganesh M. Shankar,Shaomin Li,Tapan Mehta,Amaya Garcia-Munoz,Nina E. Shepardson,Imelda M. Smith,Francesca Brett,Michael A. Farrell,Michael J. Rowan,Cynthia A. Lemere,Ciaran M. Regan,Dominic M. Walsh,Bernardo L. Sabatini,Dennis J. Selkoe +13 more
TL;DR: It is concluded that soluble Aβ oligomers extracted from Alzheimer's disease brains potently impair synapse structure and function and that dimers are the smallest synaptotoxic species.