Alzheimer's disease as homeostatic responses to age-related myelin breakdown
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TLDR
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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The connectomics of brain disorders
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The Cellular Phase of Alzheimer’s Disease
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White matter characterization with diffusional kurtosis imaging.
TL;DR: A physically meaningful interpretation of DKI metrics in white matter regions consisting of more or less parallel aligned fiber bundles is provided by modeling the tissue as two non-exchanging compartments, the intra-axonal space and extra-AXonal space.
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Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer's Disease.
Wei Ting Chen,Wei Ting Chen,Ashley Lu,Ashley Lu,Katleen Craessaerts,Katleen Craessaerts,Benjamin Pavie,Carlo Sala Frigerio,Carlo Sala Frigerio,Carlo Sala Frigerio,Nikky Corthout,Xiaoyan Qian,Jana Lalakova,Malte Kühnemund,Iryna Voytyuk,Iryna Voytyuk,Leen Wolfs,Leen Wolfs,Renzo Mancuso,Renzo Mancuso,Evgenia Salta,Evgenia Salta,Sriram Balusu,Sriram Balusu,An Snellinx,An Snellinx,Sebastian Munck,Aleksandra Jurek,José Fernández Navarro,Takaomi C. Saido,Inge Huitinga,Inge Huitinga,Joakim Lundeberg,Mark Fiers,Mark Fiers,Mark Fiers,Bart De Strooper,Bart De Strooper,Bart De Strooper +38 more
TL;DR: Genome-wide spatial transcriptomics analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.
References
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Involvement of β-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity
Huifang Ma,Sylvain Lesné,Linda Kotilinek,Jill Steidl-Nichols,Jill Steidl-Nichols,Mathew A. Sherman,Linda H. Younkin,Steven G. Younkin,Colleen L. Forster,Nicolas Sergeant,André Delacourte,Robert Vassar,Martin Citron,Paulo Kofuji,Linda M. Boland,Linda M. Boland,Karen H. Ashe,Karen H. Ashe +17 more
TL;DR: In vitro work indicates that BACE1-mediated cleavage of APP can facilitate learning, memory, and synaptic plasticity, and in vivo work shows enhanced synaptic Plasticity in the hippocampus that depends on prior synaptic activity.
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Relative Increase in Alzheimer’s Disease of Soluble Forms of Cerebral Aβ Amyloid Protein Precursor Containing the Kunitz Protease Inhibitory Domain
Robert D. Moir,Toni Lynch,Ashley I. Bush,Scott Whyte,Anna Henry,Stuart Portbury,Gerd Multhaup,David H. Small,Rudolph E. Tanzi,Konrad Beyreuther,Colin L. Masters +10 more
TL;DR: An imbalance of isoforms as one possible mechanism for amyloid deposition in sporadic AD is supported, and KPI-containing species of APP may be more amyloidsogenic.
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Apolipoprotein E polymorphism and silent microangiopathy-related cerebral damage. Results of the Austrian Stroke Prevention Study.
Reinhold Schmidt,Helena Schmidt,Franz Fazekas,Martin Schumacher,Kurt Niederkorn,Peter Kapeller,Viktor Weinrauch,Gert M. Kostner +7 more
TL;DR: These data suggest an association between the apoE epsilon 2/epsilon 3 genotype and MARCD despite favorable effects on the lipid profile and cardiac disease.
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Apolipoprotein E affects both myelin breakdown and cognition: implications for age-related trajectories of decline into dementia.
George Bartzokis,George Bartzokis,Po H. Lu,Po H. Lu,Daniel H. Geschwind,Kathleen Tingus,Danny Huang,Mario F. Mendez,Mario F. Mendez,Nancy Edwards,Nancy Edwards,Jim Mintz +11 more
TL;DR: A specific association between CPS and myelin breakdown in LMwm exists in asymptomatic "younger-old" individuals at increased genetic risk for AD, and this finding lends support to the hypotheses thatmyelin breakdown underlies age-related slowing in CPS and that by altering the trajectory ofMyelin breakdown, ApoE alleles shift the age at onset of cognitive decline.
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In vivo restoration of physiological levels of truncated TrkB.T1 receptor rescues neuronal cell death in a trisomic mouse model.
Susan G. Dorsey,Cynthia L. Renn,Laura Carim-Todd,Colleen Barrick,Linda L. Bambrick,Bruce K. Krueger,Christopher W. Ward,Lino Tessarollo +7 more
TL;DR: Restoration of the physiological level of the TrkB is shown and T1 receptor by gene targeting rescues Ts16 cortical cell and hippocampal neuronal death and corrects resting Ca2+ levels and restores BDNF-induced intracellular signaling mediated by full-length TrkB in Ts16 hippocampal neurons.