Kinetic fingerprints differentiate anti-Aβ therapies

2019 ◽  
Author(s):  
Sara Linse ◽  
Tom Scheidt ◽  
Katja Bernfur ◽  
Michele Vendruscolo ◽  
Christopher M. Dobson ◽  
...  
Keyword(s):  
Self Assembly ◽  
Clinical Stage ◽  
Amyloid Β ◽  
Therapeutic Agents ◽  
Mechanisms Of Action ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
The Past ◽  
Amyloid Cascade ◽  
Oligomeric Forms

The amyloid cascade hypothesis, according to which the self-assembly of amyloid-β peptide (Aβ) is a causative process in Alzheimer’s disease, has driven many therapeutic efforts for the past 20 years. Failures of clinical trials investigating Aβ-targeted therapies have been interpreted as evidence against this hypothesis, irrespective of the characteristics and mechanisms of action of the therapeutic agents, which are highly challenging to assess. We bring together kinetic analysis with quantitative binding measurements to address the mechanisms of action of four clinical stage anti-Aβ antibodies, aducanumab, gantenerumab, bapineuzumab and solanezumab. We reveal and quantify the striking differences of these antibodies on the aggregation kinetics and on the production of oligomeric aggregates, and link these effects to the affinity and stoichiometry of each antibody for monomeric and fibrillar forms of Aβ. Our results uncover that, uniquely amongst these four antibodies, aducanumab dramatically reduces the flux of oligomeric forms of Aβ.

Amyloid β-peptide and Alzheimer's disease

2014 ◽  
Vol 56 ◽  
pp. 99-110 ◽  
Author(s):  
David Allsop ◽  
Jennifer Mayes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Senile Plaques ◽  
Strong Support ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Amyloid Cascade Hypothesis ◽  
Sequence Of Events ◽  
Aβ Amyloid ◽  
Amyloid Cascade

One of the hallmarks of AD (Alzheimer's disease) is the formation of senile plaques in the brain, which contain fibrils composed of Aβ (amyloid β-peptide). According to the ‘amyloid cascade’ hypothesis, the aggregation of Aβ initiates a sequence of events leading to the formation of neurofibrillary tangles, neurodegeneration, and on to the main symptom of dementia. However, emphasis has now shifted away from fibrillar forms of Aβ and towards smaller and more soluble ‘oligomers’ as the main culprit in AD. The present chapter commences with a brief introduction to the disease and its current treatment, and then focuses on the formation of Aβ from the APP (amyloid precursor protein), the genetics of early-onset AD, which has provided strong support for the amyloid cascade hypothesis, and then on the development of new drugs aimed at reducing the load of cerebral Aβ, which is still the main hope for providing a more effective treatment for AD in the future.

Making and Remaking Alzheimer Disease

2013 ◽  
Author(s):  
Margaret Lock
Keyword(s):  
Alzheimer Disease ◽  
Normal Aging ◽  
Research Paradigm ◽  
Amyloid Cascade Hypothesis ◽  
The Past ◽  
Localization Theory ◽  
Initial Identification ◽  
Aging Populations ◽  
Amyloid Cascade

This chapter focuses on the “discovery” of Alzheimer disease (AD) and a somewhat condensed genealogy of its history to the present time. Emphasis is given to the virtual disappearance of AD for over four decades after its initial identification, followed by its rediscovery in the late 1960s in association with government and medical recognition of aging populations and their impending burden on society. The chapter also discusses the consolidation of what has been the dominant research paradigm in AD research for the past four decades-the amyloid cascade hypothesis, grounded in localization theory. Throughout the study, difficulties in attempting to unravel the entanglement of “normal” aging from dementia, evident from Alois Alzheimer's time, are pointed out.

scholarly journals Inhibition of the Self-Assembly of Aβ and of Tau by Polyphenols: Mechanistic Studies

Molecules ◽  
2019 ◽  
Vol 24 (12) ◽  
pp. 2316 ◽  
Author(s):  
Qiuchen Zheng ◽  
Micheal T. Kebede ◽  
Merc M. Kemeh ◽  
Saadman Islam ◽  
Bethany Lee ◽  
...  
Keyword(s):  
Self Assembly ◽  
Complex Disease ◽  
Red Wine ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Therapeutic Agents ◽  
Mechanistic Studies ◽  
Naturally Occurring ◽  
Aβ Oligomerization ◽  
Β Sheet

The amyloid-β (Aβ) peptide and tau protein are thought to play key neuropathogenic roles in Alzheimer’s disease (AD). Both Aβ and tau self-assemble to form the two major pathological hallmarks of AD: amyloid plaques and neurofibrillary tangles, respectively. In this review, we show that naturally occurring polyphenols abundant in fruits, vegetables, red wine, and tea possess the ability to target pathways associated with the formation of assemblies of Aβ and tau. Polyphenols modulate the enzymatic processing of the amyloid-β precursor protein and inhibit toxic Aβ oligomerization by enhancing the clearance of Aβ42 monomer, modulating monomer–monomer interactions and remodeling oligomers to non-toxic forms. Additionally, polyphenols modulate tau hyperphosphorylation and inhibit tau β-sheet formation. The anti-Aβ-self-assembly and anti-tau-self-assembly effects of polyphenols increase their potential as preventive or therapeutic agents against AD, a complex disease that involves many pathological mechanisms.

Enhanced self-assembly of the 7–12 sequence of amyloid-β peptide by tyrosine bromination

2020 ◽  
Vol 32 (4) ◽  
pp. 247-255 ◽  
Author(s):  
Daniele Maiolo ◽  
Andrea Pizzi ◽  
Alessandro Gori ◽  
Greta Bergamaschi ◽  
Claudia Pigliacelli ◽  
...  
Keyword(s):  
Self Assembly ◽  
Amyloid Β ◽  
Amyloid Β Peptide

Echinacoside ameliorates the memory impairment and cholinergic deficit induced by amyloid beta peptides via the inhibition of amyloid deposition and toxicology

2017 ◽  
Vol 8 (6) ◽  
pp. 2283-2294 ◽  
Author(s):  
Young-Ji Shiao ◽  
Muh-Hwan Su ◽  
Hang-Ching Lin ◽  
Chi-Rei Wu
Keyword(s):  
Amyloid Beta ◽  
Memory Impairment ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Protective Effects ◽  
Neuronal Function ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Amyloid Cascade

This study investigates the role of the amyloid cascade and central neuronal function on the protective effects of echinacoside in amyloid β peptide 1-42 (Aβ 1-42)-treated SH-SY5Y cells and an Aβ 1-42-infused rat.

scholarly journals TRPA1 channels promote astrocytic Ca2+ hyperactivity and synaptic dysfunction mediated by oligomeric forms of amyloid-β peptide

2017 ◽  
Vol 12 (1) ◽  
Author(s):  
Anthony Bosson ◽  
Adrien Paumier ◽  
Sylvie Boisseau ◽  
Muriel Jacquier-Sarlin ◽  
Alain Buisson ◽  
...  
Keyword(s):  
Amyloid Β ◽  
Synaptic Dysfunction ◽  
Amyloid Β Peptide ◽  
Oligomeric Forms
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