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Alzheimer's disease: which type of amyloid-preventing drug agents to employ?

ABSTRACT: The current paradigm in the amyloid hypothesis brands small ?-amyloid (A?) oligomers as the toxic species in Alzheimer's disease (AD). These oligomers are fibril-like; contain ?-sheet structure, and present exposed hydrophobic surface. Oligomers with this motif are capable of penetrating the cell membrane, gathering to form toxic ion channels. Current agents suppressing precursor A? cleavage have only met partial success; and to date, those targeting the peptides and their assemblies in the aqueous environment of the extracellular space largely fail in clinical trials. One possible reason is failure to reach membrane-embedded targets of disease-'infected' cells. Here we provide an overview, point to the need to account for the lipid environment when aiming to prevent the formation of toxic channels, and propose a combination therapy to target the species spectrum.

SUBMITTER: Jang H

PROVIDER: S-EPMC3663909 | biostudies-literature | 2013 Jun

REPOSITORIES: biostudies-literature

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Alzheimer's disease: which type of amyloid-preventing drug agents to employ?

Jang Hyunbum H Connelly Laura L Arce Fernando Teran FT Ramachandran Srinivasan S Lal Ratnesh R Kagan Bruce L BL Nussinov Ruth R

Physical chemistry chemical physics : PCCP 20130228 23

The current paradigm in the amyloid hypothesis brands small β-amyloid (Aβ) oligomers as the toxic species in Alzheimer's disease (AD). These oligomers are fibril-like; contain β-sheet structure, and present exposed hydrophobic surface. Oligomers with this motif are capable of penetrating the cell membrane, gathering to form toxic ion channels. Current agents suppressing precursor Aβ cleavage have only met partial success; and to date, those targeting the peptides and their assemblies in the aque ...[more]

PMID: 23450150

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Repurposed agents in the Alzheimer's disease drug development pipeline.

Project description:BackgroundTreatments are needed to address the growing prevalence of Alzheimer's disease (AD). Clinical trials have failed to produce any AD drugs for Food and Drug Administration (FDA) approval since 2003, and the pharmaceutical development process is both time-consuming and costly. Drug repurposing provides an opportunity to accelerate this process by investigating the AD-related effects of agents approved for other indications. These drugs have known safety profiles, pharmacokinetic characterization, formulations, doses, and manufacturing processes.MethodsWe assessed repurposed AD therapies represented in Phase I, Phase II, and Phase III of the current AD pipeline as registered on ClinicalTrials.gov as of February 27, 2020.ResultsWe identified 53 clinical trials involving 58 FDA-approved agents. Seventy-eight percent of the agents in trials had putative disease-modifying mechanisms of action. Of the repurposed drugs in the pipeline 20% are hematologic-oncologic agents, 18% are drugs derived from cardiovascular indications, 14% are agents with psychiatric uses, 12% are drug used to treat diabetes, 10% are neurologic agents, and the remaining 26% of drugs fall under other conditions. Intellectual property strategies utilized in these programs included using the same drug but altering doses, routes of administration, or formulations. Most repurposing trials were supported by Academic Medical Centers and were not funded through the biopharmaceutical industry. We compared our results to a European trial registry and found results similar to those derived from ClinicalTrials.gov.ConclusionsDrug repurposing is a common approach to AD drug development and represents 39% of trials in the current AD pipeline. Therapies from many disease areas provide agents potentially useful in AD. Most of the repurposed agents are generic and a variety of intellectual property strategies have been adopted to enhance their economic value.

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Natural Compound from Olive Oil Inhibits S100A9 Amyloid Formation and Cytotoxicity: Implications for Preventing Alzheimer's Disease.

Project description:Polyphenolic compounds in the Mediterranean diet have received increasing attention due to their protective properties in amyloid neurodegenerative and many other diseases. Here, we have demonstrated for the first time that polyphenol oleuropein aglycone (OleA), which is the most abundant compound in olive oil, has multiple potencies for the inhibition of amyloid self-assembly of pro-inflammatory protein S100A9 and the mitigation of the damaging effect of its amyloids on neuroblastoma SH-SY5Y cells. OleA directly interacts with both native and fibrillar S100A9 as shown by intrinsic fluorescence and molecular dynamic simulation. OleA prevents S100A9 amyloid oligomerization as shown using amyloid oligomer-specific antibodies and cross-β-sheet formation detected by circular dichroism. It decreases the length of amyloid fibrils measured by atomic force microscopy (AFM) as well as reduces the effective rate of amyloid growth and the overall amyloid load as derived from the kinetic analysis of amyloid formation. OleA disintegrates already preformed fibrils of S100A9, converting them into nonfibrillar and nontoxic aggregates as revealed by amyloid thioflavin-T dye binding, AFM, and cytotoxicity assays. At the cellular level, OleA targets S100A9 amyloids already at the membranes as shown by immunofluorescence and fluorescence resonance energy transfer, significantly reducing the amyloid accumulation in GM1 ganglioside containing membrane rafts. OleA increases overall cell viability when neuroblastoma cells are subjected to the amyloid load and alleviates amyloid-induced intracellular rise of reactive oxidative species and free Ca2+. Since S100A9 is both a pro-inflammatory and amyloidogenic protein, OleA may effectively mitigate the pathological consequences of the S100A9-dependent amyloid-neuroinflammatory cascade as well as provide protection from neurodegeneration, if used within the Mediterranean diet as a potential preventive measure.

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Neuronal microRNA response to Alzheimer's disease amyloid beta

Project description:In neurodegenerative disorders such as Alzheimer’s disease (AD), brain miRNA profiles are altered; thus miRNA dysfunction could be both a cause and a consequence of disease. Our study dissects the complexity of human AD pathology, in the absence of a post mortem delay, and provides the first miRNA profiling analysis addressing the contribution of amyloid-β (Aβ), a known causative factor of AD, to the de-regulation of neuronal miRNA expression. We used murine primary hippocampal neurons to show that Aβ is a powerful regulator of mature miRNA expression and a prominent miRNA down-regulation is evoked in response to Aβ peptides. Our study provides insight into a previously unexplored mechanism of how Aβ may impact the pathology of AD and identification of key miRNAs affected by Aβ will allow further analysis on target genes and biological pathways contributing to AD pathomechanisms.

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A Multilevel Study of Eupatorin and Scutellarein as Anti-Amyloid Agents in Alzheimer's Disease.

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Amyloid-beta Citrullination in Alzheimer's Disease

Project description:Amyloid-beta peptides which aggregate and accumulate in Alzheimer’s disease (AD) brain are known to have sequential N-terminal truncations and multiple post-translational modifications (PTM) such as isomerization, pyroglutamate formation, phosphorylation, nitration and dityrosine cross-linking. Here we add to the list of PTM citrullination (deimination) of Arg5 residue in plaque-derived Abeta in sporadic AD brains, identified by tandem mass spectrometry. We quantitated the level of citrullination on multiple N-truncated Abeta isoforms present in plaque-associated fractions and found that almost 30 % of pyroGlu3-Abeta pool was citrullinated in plaques from AD temporal cortex. We also documented citrullinated Abeta peptides in the detergent insoluble fractions from AD frontal cortex with ~ 22 % citrullination in the pyroGlu3-Abeta pool. Citrullination of Abeta is a common PTM, closely associated with pyroglutamate-Abeta formation and Abeta accumulation in AD. This may have implications for Abeta toxicity, auto-antigenicity of Abeta, and may be relevant for the design of diagnostic assays and therapeutic targeting.

2021-11-24 | PXD025620 | Pride

Beta Amyloid toxicity in a Caenorhabditis elegans model of Alzheimer's disease

Project description:Transgenic animals were engineered to express human amyloid peptide controlled by a muscle-specific, heat-inducible promoter. At low temperatures (16°C) Abeta expression is minimal, while at higher temperatures (20-25°C) Abeta accummulates in large quantities and causes paralysis. GFP- and GFP::degron (a toxic aggregating GFP mutant)-expressing animals were used as controls. Animals were grown at 16°C till early 3rd larval stage and then upshifted to 25°C. Animals were harvested at the time of upshift (T0), and every 4 hours later until 20 hours postupshift (T4-T20).

2015-02-12 | E-GEOD-65851 | biostudies-arrayexpress

Computer-Aided Drug Design Applied to Marine Drug Discovery: Meridianins as Alzheimer's Disease Therapeutic Agents.

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Project description:Alzheimer's disease (AD) is a neurodegenerative old age disease that is complex, multifactorial, unalterable, and progressive in nature. The currently approved therapy includes cholinesterase inhibitors, NMDA-receptor antagonists and their combination therapy provides only temporary symptomatic relief. Sincere efforts have been made by the researchers globally to identify new targets, discover, and develop novel therapeutic agents for the treatment of AD. This brief review article is intended to cover the recent advances in drug development and emerging therapeutic agents for AD acting at different targets. The article is compiled using various scientific online databases and by referring to clinicaltrials.gov and ALZFORUM (alzforum.org) websites. The upcoming therapies act on one or more targets including amyloids (secretases, Aβ42 production, amyloid deposition, and immunotherapy), tau proteins (tau phosphorylation/aggregation and immunotherapy) and neuroinflammation in addition to other miscellaneous targets. Despite the tremendous improvement in our understanding of the underlying pathophysiology of AD, only aducanumab was approved by FDA for the treatment of AD in 18 years i.e., since 2003. Hence, it is concluded that novel therapeutic strategies are required to discover and develop therapeutic agents to fight against the century old AD.

| S-EPMC8236749 | biostudies-literature

?-Amyloid peptides and amyloid plaques in Alzheimer's disease.

Project description:Many lines of evidence support that ?-amyloid (A?) peptides play an important role in Alzheimer's disease (AD), the most common cause of dementia. But despite much effort the molecular mechanisms of how A? contributes to AD remain unclear. While A? is generated from its precursor protein throughout life, the peptide is best known as the main component of amyloid plaques, the neuropathological hallmark of AD. Reduction in A? has been the major target of recent experimental therapies against AD. Unfortunately, human clinical trials targeting A? have not shown the hoped-for benefits. Thus, doubts have been growing about the role of A? as a therapeutic target. Here we review evidence supporting the involvement of A? in AD, highlight the importance of differentiating between various forms of A?, and suggest that a better understanding of A?'s precise pathophysiological role in the disease is important for correctly targeting it for potential future therapy.

| S-EPMC4322079 | biostudies-other

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