A Century of Alzheimer's Disease

Goedert, Michel; Spillantini, Maria Grazia

doi:10.1126/science.1132814

Cited by 1,771 publications

(1,380 citation statements)

References 79 publications

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“…IR spectra were recorded on a Varian 640-IR spectrometer in KBr disks. 1 . Samples were infused from a 100 mL Hamilton syringe at flow rate range from 5 to 10 mL/min, depending on the sample.…”

Section: Experimental Protocolsmentioning

confidence: 99%

“…Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the central nervous system (CNS), characterized by deposits of aberrant proteins namely b-amyloid (Ab) and s-protein, oxidative stress, loss of synapses and death of cholinergic neurons [1]. The etiopathogenesis of AD still remains unknown although, in the last decades, several involved factors have been identified and found consistent with its onset.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

Costa

Lopes

Russowsky

et al. 2013

European Journal of Medicinal Chemistry

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a b s t r a c tA novel series of tacrine-lophine hybrids was synthesized and tested for their ability to inhibit acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC 50 in the nanomolar concentration scale. The key step is the one-pot four component condensation reaction of 9-aminoalkylamino-1,2,3,4-tetrahydroacridines, benzil, different substituted aromatic aldehydes and NH 4 OAc, using InCl 3 as the best catalyst. Tacrine-lophine hybrids were found to be potent and selective inhibitors of cholinesterases. As an extension of the four component approach to tetrasubstituted imidazoles, a new series of bis-(2,4,5-triphenyl-1H-imidazoles) or bis(n)-lophines was tested against AChE and BuChE.

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Section: Experimental Protocolsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

Costa

Lopes

Russowsky

et al. 2013

European Journal of Medicinal Chemistry

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“…The accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles characterizes AD pathology [123], and fibrillar protein deposits can be found in many, if not all, protein misfolding diseases [1]. However, as aggregation intermediates are the likely culprits in proteotoxicity [46], it should be possible to reduce toxicity by promoting the formation of larger fibrillar aggregates at the expense of oligomeric intermediates.…”

Section: Reducing Proteotoxicity By Promoting Fibril Formationmentioning

confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

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Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

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“…Similarly, it is thought that deamidation has a role in development of the neurofibrillary tangles that are pathognomonic for Alzheimer's disease. Neurofibrillary tangles are composed of units called paired helical filaments (45). There is evidence that these develop because of deamidation of the microtubule-binding domain of the tau protein (46).…”

Section: Asparagine Deamidation In Disease-dysregulation Of a Normalmentioning

confidence: 99%

Chronoregulation by Asparagine Deamidation

Weintraub

Deverman

2007

Sci. STKE

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Every asparagine in every protein undergoes nonenzymatic deamidation to aspartate or isoaspartate at a rate determined by the surrounding protein structure and cellular environment. Under physiologic conditions, the deamidation half-life of individual asparagines in proteins is proposed to range from less than a day to several centuries. More than 200 proteins have been shown to undergo deamidation to a meaningful degree, and modeling predicts that hundreds more undergo deamidation at rates that have the potential to be of biological consequence. Because deamidation converts an asparagine into an aspartate or isoaspartate, it introduces a negative charge into a protein and results in the isomerization of a residue. Therefore, deamidation has the potential to change protein function. Additionally, deamidation is thought to render some proteins more susceptible to degradation. In most instances in which asparagine deamidation has been identified in vivo, it is involved in pathology. Hence, deamidation has been viewed primarily as a form of protein damage. However, the pervasiveness and evolutionary persistence of these unstable asparagines suggest that they may have a beneficial role. Notably, the change of even a single neighboring amino acid can have a marked effect on the rate of deamidation of an asparagine. Therefore, the underlying rate of deamidation of any asparagine is genetically programmable. This characteristic, combined with the wide range of deamidation rates that can be programmed, imparts to asparagines the potential to serve as molecular timers that regulate protein function and stability.

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A Century of Alzheimer's Disease

Cited by 1,771 publications

References 79 publications

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

Synthesis of tacrine-lophine hybrids via one-pot four component reaction and biological evaluation as acetyl- and butyrylcholinesterase inhibitors

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Chronoregulation by Asparagine Deamidation

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