Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration

Liu, Peng; Reed, Miranda N.; Kotilinek, Linda; Grant, Marianne; Forster, Colleen L.; Wang, Qiang; Shapiro, Stanley S.; Reichl, John H.; Chiang, Angie C.A.; Jankowsky, Joanna L.; Wilmot, Carrie M.; Cleary, J.; Zahs, Kathleen R.; Ashe, Karen H.

doi:10.1016/j.celrep.2015.05.021

Cited by 143 publications

(217 citation statements)

References 49 publications

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“…The recognition of this pattern suggests the possible existence of two likely pathways for the aggregation of αSyn in vivo, a principle first suggested by molecular modeling of αSyn aggregates (36) and recently integrated into the proposed mechanisms of αSyn aggregation and propagation (3). This hypothesis is further supported by the existence of divergent detections of o-αSyn by the homotypic LB509 and heterotypic LB509-A11 pairs used for the ELISA studies, as recently reported for Aβ (37). If correct, the human samples showing detection with both homotypic and heterotypic pairs would contain both conformers.…”

Section: Discussionsupporting

confidence: 58%

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

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

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Mounting evidence indicates that soluble oligomeric forms of amyloid proteins linked to neurodegenerative disorders, such as amyloid-β (Aβ), tau, or α-synuclein (αSyn) might be the major deleterious species for neuronal function in these diseases. Here, we found an abnormal accumulation of oligomeric αSyn species in AD brains by custom ELISA, size-exclusion chromatography, and nondenaturing/denaturing immunoblotting techniques. Importantly, the abundance of αSyn oligomers in human brain tissue correlated with cognitive impairment and reductions in synapsin expression. By overexpressing WT human αSyn in an AD mouse model, we artificially enhanced αSyn oligomerization. These bigenic mice displayed exacerbated Aβ-induced cognitive deficits and a selective decrease in synapsins. Following isolation of various soluble αSyn assemblies from transgenic mice, we found that in vitro delivery of exogenous oligomeric αSyn but not monomeric αSyn was causing a lowering in synapsin-I/II protein abundance. For a particular αSyn oligomer, these changes were either dependent or independent on endogenous αSyn expression. Finally, at a molecular level, the expression of synapsin genes SYN1 and SYN2 was down-regulated in vivo and in vitro by αSyn oligomers, which decreased two transcription factors, cAMP response element binding and Nurr1, controlling synapsin gene promoter activity. Overall, our results demonstrate that endogenous αSyn oligomers can impair memory by selectively lowering synapsin expression.α-synuclein | oligomer | memory | Alzheimer's disease | synapsins

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Section: Discussionsupporting

confidence: 58%

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Larson

Greimel

Amar

et al. 2017

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

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“…The two oligomers share similar sizes and a substantially unfolded secondary structure, but interact differently with the A11 antibodies and display distinct toxic properties, as a consequence of their structural differences, in particular their different levels of solvent-exposed hydrophobicity [41,52]. Our findings show that the different toxicities of the two types of oligomers are strictly dependent on the GM1 content in the neuronal membranes they interact with.…”

Section: Discussionmentioning

confidence: 62%

“…Amongst them, two types of small soluble A␤ 42 oligomers have been recently shown to possess similar size, similarly unfolded secondary structure, but distinct toxic properties, as a consequence of their structural differences [41,52]. We prepared in vitro these alternative conformers of A␤ 42 oligomers (named A+ and A-) using different conditions of aggregation according to the protocol of Ladiwala et al [41].…”

Section: Harmless Aβ 42 Oligomers Become Toxic In Gm1-enriched Neuronmentioning

confidence: 99%

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

Cascella

Evangelisti

Bigi

et al. 2017

JAD

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Abstract. An altered distribution of membrane gangliosides (GM), including GM1, has recently been reported in the brains of Alzheimer's disease (AD) patients. Moreover, amyloid-positive synaptosomes obtained from AD brains were found to contain high-density GM1 clusters, suggesting a pathological significance of GM1 increase at presynaptic neuritic terminals in AD. Here, we show that membrane GM1 specifically recruits small soluble oligomers of the 42-residue form of amyloid-␤ peptide (A␤ 42 ), with intracellular flux of Ca 2+ ions in primary rat hippocampal neurons and in human neuroblastoma cells. Specific membrane proteins appear to be involved in the early and transient influx of Ca 2+ ions induced by A␤ 42 oligomers with high solvent-exposed hydrophobicity (A+), but not in the sustained late influx of the same oligomers and in that induced by A␤ 42 oligomers with low solvent-exposed hydrophobicity (A−) in GM1-enriched cells. In addition, A+ oligomers accumulate in proximity of membrane NMDA and AMPA receptors, inducing the early and transient Ca 2+ influx, although FRET shows that the interaction is not direct. These results suggest that age-dependent clustering of GM1 within neuronal membranes could induce neurodegeneration in elderly people as a consequence of an increased ability of the lipid bilayers to recruit membrane-permeabilizing oligomers. We also show that both lipid and protein components of the plasma membrane can contribute to neuronal dysfunction, thus expanding the molecular targets for therapeutic intervention in AD.

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“…Type 1 oligomers appear early, are widely spread throughout the brain, correlate to cognitive deficits and can be stained with the oligomeric specific antibody A11 [84]. In contrast, type 2 oligomers have the structure of Aβ fibrils with parallel β-sheets, appear after plaques are formed through secondary nucleation, are in close vicinity to the plaques, are relatively innocuous and are stained by the antibody OC which detects amyloid fibrils [225]. Our results indicate that p-FTAA induces formation of oligomers of type 2 that are rich in β-sheet structure, since Aβ together with p-FTAA was OC-positive already at the start of the aggregation process, as revealed by dense dots, whereas Aβ aggregated alone only displayed a faint OC signal.…”

Section: Paper Iv: Lysozyme Attenuates the Cellular Uptake Of Amyloid-βmentioning

confidence: 99%

“…Similar to the uptake study, lysozyme that cooligomerized with Aβ showed the most effective protection ( Figure 20B). It was recently reported in mice that there are two broad classes of Aβ oligomers: prefibrillar and fibrillar oligomers, referred to as type 1 and type 2 oligomers, respectively [225]. Type 1 oligomers appear early, are widely spread throughout the brain, correlate to cognitive deficits and can be stained with the oligomeric specific antibody A11 [84].…”

Section: Paper Iv: Lysozyme Attenuates the Cellular Uptake Of Amyloid-βmentioning

confidence: 99%

The influence of lysozyme and oligothiophenes on amyloid-β toxicity in models of Alzheimer’s disease

Sandin¹

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Alzheimer’s disease (AD) is a neurodegenerative disease and the most common cause of dementia worldwide. Apart from dominantly inherited mutations, age is the major risk factor and as life expectancy increases the prevalence for AD escalates dramatically. AD causes substantial problems for the affected persons and their families, and the society suffers economically. To date the available treatments only temporarily relieve the symptoms, wherefore the development of a cure is of utmost importance. The etiology of AD is still inconclusive but many believe that small aggregates (oligomers) of the protein amyloid-β (Aβ) are central for the onset of AD. The aims of this thesis were to investigate how different molecules affect the aggregation and toxicity of Aβ. In paper I and II, two oligothiophenes were studied; p-FTAA and h-FTAA and in paper III and IV the inflammatory protein lysozyme was explored. Differentiated neuroblastoma cells and Drosophila melanogaster were used as models of AD to address the issue. The results show that p-FTAA rescues neuroblastoma cells from Aβ toxicity when Aβ is coaggregated with lysozyme. Various biophysical studies show that the co-aggregation increases the formation of fibrillar Aβ structures rich in β-sheets. Noteworthy, these Aβ fibrils were more resistant to both degradation and denaturation, and less prone to propagate seeding from Aβ monomers. Furthermore, h-FTAA, but not p-FTAA, was able to protect neuroblastoma cell toxicity when exposed to Aβ with the Arctic mutation (AβArc), which probably reflects the weaker binding of AβArc to p-FTAA, compared to h-FTAA. Lysozyme levels were increased in CSF from patients that were both biochemically and clinically diagnosed with AD. In mice models of AD it was revealed that the mRNA increase in lysozyme correlates to increased Aβ pathology, but not to tau pathology, indicating that Aβ could drive the expression of lysozyme. To evaluate the effect for increased expression of lysozyme, co-expression of lysozyme was achieved in flies that expressed Aβ in the retina of the eyes, or in flies that expressed AβArc in the central nervous system. In all AD fly models, co-expression of lysozyme protected the cells from the Aβ induced toxicity. Of note, flies that expressed the toxic AβArc in the CNS of the flies showed an improvement in both lifespan and activity. Finally, we demonstrate that Aβ aggregating in the presence of lysozyme inhibits the cellular uptake of Aβ and also the cytotoxic effect of Aβ. The work included in this thesis demonstrates that the oligothiophenes p-FTAA and h-FTAA, and also lysozyme have the potential to be used as treatment strategies for sporadic AD, but remarkable, also in familial AD with the highly toxic Arctic mutation. The protective mechanism of p-FTAA seems to be attributed to the ability to generate stable Aβ fibrils with reduced seeding capacity, and that lysozyme inhibits the neuronal uptake of Aβ, which could prevent both the intracellular toxicity and cell-to-cell transmission of Aβ.

Funded by: Stiftel...

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Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration

Cited by 143 publications

References 49 publications

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Selective lowering of synapsins induced by oligomeric α-synuclein exacerbates memory deficits

Soluble Oligomers Require a Ganglioside to Trigger Neuronal Calcium Overload

The influence of lysozyme and oligothiophenes on amyloid-β toxicity in models of Alzheimer’s disease

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