Pharmacotherapies for Alzheimer's disease: Beyond cholinesterase inhibitors

Tayeb, Haythum O.; Yang, Hyun Duk; Price, Bruce H.; Tarazi, Frank I.

doi:10.1016/j.pharmthera.2011.12.002

Cited by 189 publications

(154 citation statements)

References 285 publications

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“…A formation and aggregation are thought to trigger a cascade of deleterious events that eventually result in neuronal dysfunction and death and dementia. Thus, the discovery of inhibitors of A aggregation is an area of very active research [2,6,[13][14][15][16], together with that of other A-directed drug candidates aimed at reducing the levels of A in brain by inhibiting its formation (inhibitors of -and -secretases) or by increasing its clearance (active or passive immunotherapy), in the search for effective medications that can delay the onset of AD and slow or halt its progression [16,17].…”

Section: Introductionmentioning

confidence: 99%

Thioflavin-S Staining of Bacterial Inclusion Bodies for the Fast, Simple, and Inexpensive Screening of Amyloid Aggregation Inhibitors

Pouplana¹,

Espargaró²,

Galdeano³

et al. 2014

CMC

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Section: Introductionmentioning

confidence: 99%

Thioflavin-S Staining of Bacterial Inclusion Bodies for the Fast, Simple, and Inexpensive Screening of Amyloid Aggregation Inhibitors

Pouplana¹,

Espargaró²,

Galdeano³

et al. 2014

CMC

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“…3,4 Current therapeutics largely target the breakdown of acetylcholine but are unable to halt the advancement of the disease. 5 Due to the central role of Aβ aggregation in the progression of Alzheimer's disease, inhibiting the aggregation cascade is an attractive approach for therapeutic development. Efforts have been made over many years to study different classes of small molecules and peptides that may interfere with the formation of higher-order Aβ species that may be neurotoxic.…”

mentioning

confidence: 99%

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

Lemkul

Bevan

2012

ACS Chem. Neurosci.

102

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The pathogenic aggregation of the amyloid β-peptide (Aβ) is considered a hallmark of the progression of Alzheimer's disease, the leading cause of senile dementia in the elderly and one of the principal causes of death in the United States. In the absence of effective therapeutics, the incidence and economic burden associated with the disease are expected to rise dramatically in the coming decades. Targeting Aβ aggregation is an attractive therapeutic approach, though structural insights into the nature of Aβ aggregates from traditional experiments are elusive, making drug design difficult. Theoretical methods have been used for several years to augment experimental work and drive progress forward in Alzheimer's drug design. In this Review, we will describe how two common techniques, molecular docking and molecular dynamics simulations, are being applied in developing small molecules as effective therapeutics against monomeric, oligomeric, and fibrillated forms of Aβ. Recent successes and important limitations will be discussed, and we conclude by providing a perspective on the future of this field by citing recent examples of sophisticated approaches used to better characterize interactions of small molecules with Aβ and other amyloidogenic proteins.

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“…29 Compounds that specifically bind Aβ have been shown to be neuroprotective. 30 Herein we have explored the effects of the amyloid peptides Aβ, PrP, A-Bri, A-Dan, and IAPP on the release of KP and KP 45−54 from human SH-SY5Y neuronal cultures 31 and studied the effects of KiSS-1 and KP peptides on the toxicity of amyloid peptides. The effects of KP peptides on Aβ, PrP, A-Bri, A-Dan, and IAPP toxicity in human SH-SY5Y neuronal cultures 31 and rat cortical neuron cultures 32,33 have been characterized.…”

mentioning

confidence: 99%

Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

Milton

Chilumuri

Rocha‐Ferreira

et al. 2012

ACS Chem. Neurosci.

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Alzheimer's disease (AD) onset is associated with changes in hypothalamic-pituitary−gonadal (HPG) function. The 54 amino acid kisspeptin (KP) peptide regulates the HPG axis and alters antioxidant enzyme expression. The Alzheimer's amyloid-β (Aβ) is neurotoxic, and this action can be prevented by the antioxidant enzyme catalase. Here, we examined the effects of KP peptides on the neurotoxicity of Aβ, prion protein (PrP), and amylin (IAPP) peptides. The Aβ, PrP, and IAPP peptides stimulated the release of KP and KP 45−54. The KP peptides inhibited the neurotoxicity of Aβ, PrP, and IAPP peptides, via an action that could not be blocked by kisspeptin-receptor (GPR-54) or neuropeptide FF (NPFF) receptor antagonists. Knockdown of KiSS-1 gene, which encodes the KP peptides, in human neuronal SH-SY5Y cells with siRNA enhanced the toxicity of amyloid peptides, while KiSS-1 overexpression was neuroprotective. A comparison of the catalase and KP sequences identified a similarity between KP residues 42−51 and the region of catalase that binds Aβ. The KP peptides containing residues 45−50 bound Aβ, PrP, and IAPP, inhibited Congo red binding, and were neuroprotective. These results suggest that KP peptides are neuroprotective against Aβ, IAPP, and PrP peptides via a receptor independent action involving direct binding to the amyloid peptides. KEYWORDS: KiSS-1, kisspeptin, amyloid-β, prion protein, amylin, neuroprotection N euroendocrine hormone changes are seen in aging, and there are disease specific changes associated with Alzheimer's disease (AD). 1,2 One of the neuroendocrine systems to show profound changes with aging is the hypothalamic−pituitary−gonadal (HPG) system, and the pathology of AD, Creutzfeldt−Jakob disease (CJD), and type 2 diabetes mellitus (T2DM) is also associated with changes in the hormones of this system. 3,4 A major regulator of the HPGaxis is the 54 amino acid kisspeptin (KP) peptide, which acts on gonadotrophin-releasing hormone (GnRH) neurons to activate GnRH release. 5 The KP peptide is produced in neurons by processing of the KiSS-1 preproprotein to yield the 54 amino acid KP peptide, which corresponds to residues 68−121 of KiSS-1. 6 Shorter derivatives of KP peptide comprising the C-terminal 14 (KP 41−54), 13 (KP 42−54), and 10 (KP 45−54) amino acids have also been found in tissues and corresponding to residues 108− 121, 109−121, and 112−121 of KiSS-1. 6,7 Biological activity of KP peptides requires the KP 45−54 sequence and is mediated via a specific KP receptor (GPR-54). 6,7 Lack of KP signaling via the GPR-54 receptor is associated with reproductive system failure. 8 Cleavage of the KP 45−54 peptide between residues 51 and 52 by matrix metalloproteinases abolishes the activation of GPR-54 by the KP 45−54 peptide. 9 The KP 42−54 and KP 45−54 peptides also activate NPFF receptors, 10,11 and some of the actions of KP peptides could be mediated by NPFF receptor activation.There are profound changes in KP signaling at menopause 12 and notable sex differences in hypothalamic neurodegenera...

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Pharmacotherapies for Alzheimer's disease: Beyond cholinesterase inhibitors

Cited by 189 publications

References 285 publications

Thioflavin-S Staining of Bacterial Inclusion Bodies for the Fast, Simple, and Inexpensive Screening of Amyloid Aggregation Inhibitors

Thioflavin-S Staining of Bacterial Inclusion Bodies for the Fast, Simple, and Inexpensive Screening of Amyloid Aggregation Inhibitors

The Role of Molecular Simulations in the Development of Inhibitors of Amyloid β-Peptide Aggregation for the Treatment of Alzheimer’s Disease

Kisspeptin Prevention of Amyloid-β Peptide Neurotoxicityin Vitro

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