Journal ArticleDOI
Alzheimer disease therapy—moving from amyloid-β to tau
Ezio Giacobini,Gabriel Gold +1 more
TLDR
A critical analysis of the failure of Aβ-directed therapies for Alzheimer disease is presented, limitations of the amyloid cascade hypothesis are discussed, and the potential value of tau-targeted therapy for AD is suggested.Abstract:
Disease-modifying treatments for Alzheimer disease (AD) have focused mainly on reducing levels of amyloid-β (Aβ) in the brain. Some compounds have achieved this goal, but none has produced clinically meaningful results. Several methodological issues relating to clinical trials of these agents might explain this failure; an additional consideration is that the amyloid cascade hypothesis--which places amyloid plaques at the heart of AD pathogenesis--does not fully integrate a large body of data relevant to the emergence of clinical AD. Importantly, amyloid deposition is not strongly correlated with cognition in multivariate analyses, unlike hyperphosphorylated tau, neurofibrillary tangles, and synaptic and neuronal loss, which are closely associated with memory deficits. Targeting tau pathology, therefore, might be more clinically effective than Aβ-directed therapies. Furthermore, numerous immunization studies in animal models indicate that reduction of intracellular levels of tau and phosphorylated tau is possible, and is associated with improved cognitive performance. Several tau-related vaccines are in advanced preclinical stages and will soon enter clinical trials. In this article, we present a critical analysis of the failure of Aβ-directed therapies, discuss limitations of the amyloid cascade hypothesis, and suggest the potential value of tau-targeted therapy for AD.read more
Citations
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Journal ArticleDOI
Immune attack: the role of inflammation in Alzheimer disease
TL;DR: As inflammation in AD primarily concerns the innate immune system — unlike in 'typical' neuroinflammatory diseases such as multiple sclerosis and encephalitides — the concept of neuroinflammation in AD may need refinement.
Journal ArticleDOI
Reactive Oxygen Species (ROS)-Based Nanomedicine.
Bowen Yang,Yu Chen,Jianlin Shi +2 more
TL;DR: In this article, the intrinsic biochemical properties of reactive oxygen species (ROS) underlie the mechanisms that regulate various physiological functions of living organisms, and they play an essential role in regulating various physiological function.
Journal ArticleDOI
Clearance systems in the brain—implications for Alzheimer disease
Jenna M. Tarasoff-Conway,Roxana O. Carare,Ricardo S. Osorio,Lidia Glodzik,Tracy Butler,Els Fieremans,Leon Axel,Henry Rusinek,Charles Nicholson,Berislav V. Zlokovic,Blas Frangione,Kaj Blennow,Joël Ménard,Henrik Zetterberg,Thomas Wisniewski,Mony J. de Leon +15 more
TL;DR: The clearance systems of the brain as they relate to proteins implicated in AD pathology are described, with the main focus on Aβ.
Journal ArticleDOI
Tau-targeting therapies for Alzheimer disease.
TL;DR: Therapies for Alzheimer disease in clinical trials are gradually shifting from amyloid-β (Aβ)-targeting to tau-targeting approaches, and tau is likely to be a better target than Aβ once cognitive deficits manifest because the tau burden correlates better with clinical impairments than does the Aβ burden.
Journal ArticleDOI
Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease
Fuyuki Kametani,Masato Hasegawa +1 more
TL;DR: Recent findings indicate that the main factor underlying the development and progression of AD is tau, not Aβ, and the deficiencies of the amyloid hypothesis are described.
References
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Journal ArticleDOI
Alzheimer's disease: the amyloid cascade hypothesis
John Hardy,Gerald A. Higgins +1 more
TL;DR: An extensive catalog of genes that act in a migrating cell is provided, unique molecular functions involved in nematode cell migration are identified, and similar functions in humans are suggested.
Journal ArticleDOI
Alzheimer's disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein
George G. Glenner,Caine W. Wong +1 more
TL;DR: A purified protein derived from the twisted beta-pleated sheet fibrils in cerebrovascular amyloidosis associated with Alzheimer's disease has been isolated and Amino acid sequence analysis and a computer search reveals this protein to have no homology with any protein sequenced thus far.
Journal ArticleDOI
Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid beta-peptide.
Christian Haass,Dennis J. Selkoe +1 more
TL;DR: Findings in other neurodegenerative diseases indicate that a broadly similar process of neuronal dysfunction is induced by diffusible oligomers of misfolded proteins.
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.
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