Journal ArticleDOI
Alzheimer's Disease Is a Synaptic Failure
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TLDR
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.Abstract:
In its earliest clinical phase, Alzheimer's disease characteristically produces a remarkably pure impairment of memory. 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.read more
Citations
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Toward defining the preclinical stages of Alzheimer's disease: Recommendations from the National Institute on Aging-Alzheimer's Association workgroups on diagnostic guidelines for Alzheimer's disease
Reisa A. Sperling,Paul S. Aisen,Laurel A. Beckett,David A. Bennett,Suzanne Craft,Anne M. Fagan,Takeshi Iwatsubo,Clifford R. Jack,Jeffrey Kaye,Thomas J. Montine,Denise C. Park,Eric M. Reiman,Christopher C. Rowe,Eric Siemers,Yaakov Stern,Kristine Yaffe,Maria C. Carrillo,Bill Thies,Marcelle Morrison-Bogorad,Molly V. Wagster,Creighton H. Phelps +20 more
TL;DR: A conceptual framework and operational research criteria are proposed, based on the prevailing scientific evidence to date, to test and refine these models with longitudinal clinical research studies and it is hoped that these recommendations will provide a common rubric to advance the study of preclinical AD.
Journal ArticleDOI
Triple-Transgenic Model of Alzheimer's Disease with Plaques and Tangles: Intracellular Aβ and Synaptic Dysfunction
Salvatore Oddo,Antonella Caccamo,Jason D. Shepherd,M. Paul Murphy,Todd E. Golde,Rakez Kayed,Raju Metherate,Mark P. Mattson,Yama Akbari,Frank M. LaFerla +9 more
TL;DR: The recapitulation of salient features of AD in these mice clarifies the relationships between Abeta, synaptic dysfunction, and tangles and provides a valuable model for evaluating potential AD therapeutics as the impact on both lesions can be assessed.
Journal ArticleDOI
Protein aggregation and neurodegenerative disease.
TL;DR: There is increased understanding of the pathways involved in protein aggregation, and some recent clues have emerged as to the molecular mechanisms of cellular toxicity, leading to approaches toward rational therapeutics.
Journal ArticleDOI
The classical complement cascade mediates CNS synapse elimination.
Beth Stevens,Nicola J. Allen,Luis E. Vazquez,Gareth R. Howell,Karen S. Christopherson,Navid Nouri,Kristina D. Micheva,Adrienne K. Mehalow,Andrew D. Huberman,Benjamin K. Stafford,Alexander Sher,Alan Litke,John D. Lambris,Stephen J. Smith,Simon W. M. John,Ben A. Barres +15 more
TL;DR: It is shown that C1q, the initiating protein in the classical complement cascade, is expressed by postnatal neurons in response to immature astrocytes and is localized to synapses throughout the postnatal CNS and retina, supporting a model in which unwanted synapses are tagged by complement for elimination and suggesting that complement-mediated synapse elimination may become aberrantly reactivated in neurodegenerative disease.
Journal ArticleDOI
Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy
TL;DR: The A β-dependent and Aβ-independent mechanisms that link Apo-E4 status with AD risk are discussed, and how to design effective strategies for AD therapy by targeting ApO-E is considered.
References
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Journal ArticleDOI
Mild Cognitive Impairment: Clinical Characterization and Outcome
Ronald C. Petersen,Glenn E. Smith,Stephen C. Waring,Robert J. Ivnik,Eric G. Tangalos,Emre Kokmen +5 more
TL;DR: Patients who meet the criteria for MCI can be differentiated from healthy control subjects and those with very mild AD, and appear to constitute a clinical entity that can be characterized for treatment interventions.
Journal ArticleDOI
Alzheimer's Disease: Genes, Proteins, and Therapy
TL;DR: Evidence that the presenilin proteins, mutations in which cause the most aggressive form of inherited AD, lead to altered intramembranous cleavage of the beta-amyloid precursor protein by the protease called gamma-secretase has spurred progress toward novel therapeutics and provided discrete biochemical targets for drug screening and development.
Journal ArticleDOI
Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo.
Dominic M. Walsh,Igor Klyubin,Julia V. Fadeeva,William K. Cullen,Roger Anwyl,Michael S. Wolfe,Michael J. Rowan,Dennis J. Selkoe +7 more
TL;DR: It is reported that natural oligomers of human Aβ are formed soon after generation of the peptide within specific intracellular vesicles and are subsequently secreted from the cell, indicating that synaptotoxic Aβ oligomers can be targeted therapeutically.
Journal ArticleDOI
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.
Journal ArticleDOI
Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins
Mary P. Lambert,A. K. Barlow,Brett A. Chromy,C. Edwards,R. Freed,M. Liosatos,Todd E. Morgan,Irina Rozovsky,Barbara L. Trommer,Kirsten L. Viola,Pat Wals,Chuan Zhang,Caleb E. Finch,Grant A. Krafft,William L. Klein +14 more
TL;DR: It is hypothesized that impaired synaptic plasticity and associated memory dysfunction during early stage Alzheimer's disease and severe cellular degeneration and dementia during end stage could be caused by the biphasic impact of Abeta-derived diffusible ligands acting upon particular neural signal transduction pathways.
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