Journal ArticleDOI
The toxic Aβ oligomer and Alzheimer's disease: an emperor in need of clothes
TLDR
The evidence supporting toxic Aβ oligomers as drivers of neurodegeneration is reviewed and some suggestions that might facilitate progress are made to facilitate progress in this complex field.Abstract:
The 'toxic Aβ oligomer' hypothesis has attracted considerable attention among Alzheimer's disease researchers as a way of resolving the lack of correlation between deposited amyloid-β (Aβ) in amyloid plaques-in terms of both amount and location-and cognitive impairment or neurodegeneration. However, the lack of a common, agreed-upon experimental description of the toxic Aβ oligomer makes interpretation and direct comparison of data between different research groups impossible. Here we critically review the evidence supporting toxic Aβ oligomers as drivers of neurodegeneration and make some suggestions that might facilitate progress in this complex field.read more
Citations
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Journal ArticleDOI
Neuropathological Alterations in Alzheimer Disease
TL;DR: Postmortem studies have enabled the staging of the progression of both amyloid and tangle pathologies, and the development of diagnostic criteria that are now used worldwide, and these cross-sectional neuropathological data have been largely validated by longitudinal in vivo studies using modern imaging biomarkers such as amyloids PET and volumetric MRI.
Journal ArticleDOI
The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease
Jeff Sevigny,Ping Chiao,Thierry Bussiere,Paul H. Weinreb,Leslie Williams,Marcel Maier,Robert Dunstan,Stephen Salloway,Tianle Chen,Yan Ling,John O'Gorman,Fang Qian,Mahin Arastu,Mingwei Li,Sowmya Chollate,Melanie S. Brennan,Omar Quintero-Monzon,Robert H. Scannevin,H. Moore Arnold,Thomas Engber,Kenneth J. Rhodes,James Ferrero,Yaming Hang,Alvydas Mikulskis,Jan Grimm,Christoph Hock,Roger M. Nitsch,Alfred Sandrock +27 more
TL;DR: In patients with prodromal or mild AD, one year of monthly intravenous infusions of aducanumab reduces brain Aβ in a dose- and time-dependent manner, accompanied by a slowing of clinical decline measured by Clinical Dementia Rating—Sum of Boxes and Mini Mental State Examination scores.
Journal ArticleDOI
Protein Misfolding, Amyloid Formation, and Human Disease: A Summary of Progress Over the Last Decade
TL;DR: This review describes this field of science with particular reference to the advances that have been made over the last decade in understanding of its fundamental nature and consequences and shows evidence that a complex proteostasis network actively combats protein aggregation.
Journal ArticleDOI
Alzheimer mechanisms and therapeutic strategies.
Yadong Huang,Lennart Mucke +1 more
TL;DR: Investigative and drug development efforts should be diversified to fully address the multifactoriality of Alzheimer's disease.
Journal ArticleDOI
The Cellular Phase of Alzheimer’s Disease
TL;DR: Evidence supporting a long, complex cellular phase consisting of feedback and feedforward responses of astrocytes, microglia, and vasculature is reviewed.
References
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Journal ArticleDOI
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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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
Common Structure of Soluble Amyloid Oligomers Implies Common Mechanism of Pathogenesis
Rakez Kayed,Elizabeth Head,Jennifer L. Thompson,Theresa M. McIntire,Saskia Milton,Carl W. Cotman,Charles G. Glabe +6 more
TL;DR: It is shown that all of the soluble oligomers tested display a common conformation-dependent structure that is unique to soluble oligomer regardless of sequence, suggesting they share a common mechanism of toxicity.
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.
Journal ArticleDOI
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.
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