The case for soluble Aβ oligomers as a drug target in Alzheimer's disease

Hefti, Franz; Goure, William F.; Jerecı̀ć, Jasna; Iverson, Kent; Walicke, Patricia A.; Krafft, Grant A.

doi:10.1016/j.tips.2013.03.002

Cited by 106 publications

(85 citation statements)

References 66 publications

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“…This explanation would be consistent with our observation of a (nonsignificant) reduction of oAb in late-stage compared with early-stage disease and with the view that amyloid plaques are predominately a sink rather than a source for soluble Ab. 2 However, plaques could still serve as local reservoirs for small oligomers, operating with a dynamic equilibrium. 77 For the oAb assay, note that the sandwich ELISA may detect multiple Ab molecules bound to an unrelated carrier protein such as a proteoglycan; this possibility should be somewhat mitigated by the use of an aqueous soluble fraction without membranes or membrane fragments.…”

Section: Discussionmentioning

confidence: 99%

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Bilousova

Miller

Poon

et al. 2016

The American Journal of Pathology

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Amyloid-b (Ab) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Ab and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Ab and p-tau in large populations of individual synaptic terminals. Soluble Ab oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Ab was elevated in patients with early-and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Ab oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Ab-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Ab drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed. (Am J Pathol 2016, 186: 185e198; http://dx.doi.org/10.1016/j.ajpath.2015 A large body of evidence indicates that soluble oligomers of amyloid-b (Ab) are the primary toxic peptides that initiate downstream tau pathology in the amyloid cascade hypothesis of Alzheimer disease (AD). 1,2 However, the time course and severity of AD dementia have been generally found to correlate with neurofibrillary tangle development rather than plaque appearance, 3e8 although a few studies have linked plaques with early cognitive decline. 9e12 Soluble oligomeric

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Section: Discussionmentioning

confidence: 99%

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Bilousova

Miller

Poon

et al. 2016

The American Journal of Pathology

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“…Indeed, there is strong evidence that the disordered oligomers rather than fully grown fibrils are the main pathogenic species in protein aggregation diseases (31-33). As such, defining the role of the prefibrillar oligomers during amyloid formation will be crucial to develop intervention strategies that target these species (1,30,34,35).Mutations in the polypeptide sequence and extrinsic changes in the experimental conditions are known to alter the concentrations of aggregated species, their size, and their cytotoxicity (25,(36)(37)(38)(39). For instance, mutations that increase hydrophobicity of the Alzheimer's β-peptide (Aβ1-42) have a pronounced effect on its aggregation behavior and the size distribution of the resulting oligomers (23)(24)(25)(26)40), promoting toxicity and expediting the fibrillization process.…”

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confidence: 99%

Crucial role of nonspecific interactions in amyloid nucleation

Šarić

Chebaro

Knowles

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

172

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Protein oligomers have been implicated as toxic agents in a wide range of amyloid-related diseases. However, it has remained unsolved whether the oligomers are a necessary step in the formation of amyloid fibrils or just a dangerous byproduct. Analogously, it has not been resolved if the amyloid nucleation process is a classical onestep nucleation process or a two-step process involving prenucleation clusters. We use coarse-grained computer simulations to study the effect of nonspecific attractions between peptides on the primary nucleation process underlying amyloid fibrillization. We find that, for peptides that do not attract, the classical one-step nucleation mechanism is possible but only at nonphysiologically high peptide concentrations. At low peptide concentrations, which mimic the physiologically relevant regime, attractive interpeptide interactions are essential for fibril formation. Nucleation then inevitably takes place through a two-step mechanism involving prefibrillar oligomers. We show that oligomers not only help peptides meet each other but also, create an environment that facilitates the conversion of monomers into the β-sheet-rich form characteristic of fibrils. Nucleation typically does not proceed through the most prevalent oligomers but through an oligomer size that is only observed in rare fluctuations, which is why such aggregates might be hard to capture experimentally. Finally, we find that the nucleation of amyloid fibrils cannot be described by classical nucleation theory: in the two-step mechanism, the critical nucleus size increases with increases in both concentration and interpeptide interactions, which is in direct contrast with predictions from classical nucleation theory.amyloid | protein aggregation | protein oligomers | neurodegeneration | coarse-grained simulations D uring the process of amyloid formation, normally soluble proteins assemble into fibrils that are enriched in β-sheet content and have diameters of a few nanometers and lengths up to several micrometers. This phenomenon has been implicated in a variety of pathogenic processes, including Alzheimer's and Parkinson's diseases, type 2 diabetes, and systemic amyloidoses (1-3). The association with human diseases has largely motivated a long-standing effort to probe the assembly process, and numerous studies have aimed at elucidating the mechanism of amyloid aggregation (4). The basic nature of the aggregation reaction has emerged as a nucleation and growth process (5, 6), where the aggregates are created through a not well-understood primary nucleation event and can grow by recruiting additional peptides or proteins to their ends (7,8). In this paper, we focus on the nature of this primary step in amyloid nucleation and the fundamental initial events that underlie amyloid formation.Amyloidogenic peptides and proteins, when in their nonpathological cellular form, can range in the structures from mainly α-helical to β-sheet and even random coil, whereas the amyloid forms of proteins possess a generic cross-β-structure ...

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“…At this level of SUVR there are sparse if any well-developed amyloid plaques, because florbetapir binds primarily if not solely to fibrillar amyloid. However, at low levels of florbetapir binding, more soluble Ab oligomers may still be present and represent the more directly neurotoxic forms of the protein, as suggested by recent studies [30][31][32][33]. If this is the case, further studies using radiologic ligands that tag more soluble amyloid peptide species may yield more robust associations with driving risk than the present study.…”

Section: Discussionmentioning

confidence: 49%

P4‐144: Brain Amyloid in Preclinical Alzheimer’s Disease is Associated with Increased Driving Risk

Ott

Jones

Noto

et al. 2016

Alzheimer's & Dementia

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Introduction: Postmortem studies suggest that fibrillar brain amyloid places people at higher risk for hazardous driving in the preclinical stage of Alzheimer's disease (AD). Methods: We administered driving questionnaires to 104 older drivers (19 AD, 24 mild cognitive impairment, and 61 cognitive normal) who had a recent 18 F-florbetapir positron emission tomography scan. We examined associations of amyloid standardized uptake value ratios with driving behaviors: traffic violations or accidents in the past 3 years. Results: The frequency of violations or accidents was curvilinear with respect to standardized uptake value ratios, peaking around a value of 1.1 (model r 2 5 0.10, P 5 .002); moreover, this relationship was evident for the cognitively normal participants. Discussion: We found that driving risk is strongly related to accumulating amyloid on positron emission tomography, and that this trend is evident in the preclinical stage of AD. Brain amyloid burden may in part explain the increased crash risk reported in older adults.

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The case for soluble Aβ oligomers as a drug target in Alzheimer's disease

Cited by 106 publications

References 66 publications

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases

Crucial role of nonspecific interactions in amyloid nucleation

P4‐144: Brain Amyloid in Preclinical Alzheimer’s Disease is Associated with Increased Driving Risk

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