Journal ArticleDOI
Therapeutic significance of NR2B-containing NMDA receptors and mGluR5 metabotropic glutamate receptors in mediating the synaptotoxic effects of β-amyloid oligomers on long-term potentiation (LTP) in murine hippocampal slices
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TLDR
It is demonstrated that glutamate receptor antagonists delivered at concentrations which still allow physiological activities in vitro, are able to prevent Aβ(1-42) oligomer-induced synaptic toxicity and further support the glutamatergic system as a target for the development of improved symptomatic/neuroprotective treatments for AD.About:
This article is published in Neuropharmacology.The article was published on 2011-05-01. It has received 150 citations till now. The article focuses on the topics: Long-term depression & Memantine.read more
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Therapeutics of Alzheimer's disease: Past, present and future.
TL;DR: The current rationales and targets evaluated for therapeutic benefit in AD are reviewed and the major developments in this direction are the amyloid and tau based therapeutics, which could hold the key to treatment of AD in the near future.
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Metabotropic Glutamate Receptor 5 Is a Coreceptor for Alzheimer Aβ Oligomer Bound to Cellular Prion Protein
Ji Won Um,Adam C. Kaufman,Mikhail A. Kostylev,Jacqueline K. Heiss,Massimiliano Stagi,Hideyuki Takahashi,Meghan E. Kerrisk,Alexander O. Vortmeyer,Thomas Wisniewski,Anthony J. Koleske,Erik C. Gunther,Haakon B. Nygaard,Stephen M. Strittmatter +12 more
TL;DR: Transmembrane PSD proteins heterologously screened for the ability to couple Aβo-PrP(C) with Fyn and found coexpression of the metabotropic glutamate receptor, mGluR5, allowed PrP (C)-bound A βo to activate Fyn.
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Alzheimer's disease, β-amyloid, glutamate, NMDA receptors and memantine – searching for the connections
Wojciech Danysz,Chris G. Parsons +1 more
TL;DR: Strong support for the clinical relevance of such interactions is provided by the NMDA receptor antagonist memantine, which offers an excellent tool to facilitate translational extrapolations from in vitro studies through in vivo animal experiments to its ultimate clinical utility.
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Extrasynaptic NMDA Receptor Involvement in Central Nervous System Disorders
TL;DR: Evidence both supporting and refuting the localization hypothesis of NMDAR function is reviewed and the role of N MDAR localization in disorders of the nervous system is discussed, particularly in Alzheimer disease and Huntington disease.
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The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease.
TL;DR: Evidence is presented that links Aβ oligomers to pathogenesis in animal models and humans, with reference to seminal discoveries from cell biology and new ideas concerning pathogenic mechanisms, including relationships to diabetes and Fragile X.
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.
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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.
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LTP and LTD: an embarrassment of riches.
Robert C. Malenka,Mark F. Bear +1 more
TL;DR: This work reviews those forms of LTP and LTD for which mechanisms have been most firmly established and examples are provided that show how these mechanisms can contribute to experience-dependent modifications of brain function.
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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.