Aβ42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-β42 species and protects synaptic structure and function

Barucker, Christian; Bittner, Heiko J.; Chang, Philip K.-Y.; Cameron, Scott A.; Hancock, Mark A.; Liebsch, Filip; Hossain, Shireen; Harmeier, Anja; Shaw, Hunter S.; Charron, François; Gensler, Manuel; Dembny, Paul; Zhuang, Wei-Qin; Schmitz, Dietmar; Rabe, Jürgen P.; Rao, Yong; Hildebrand, Peter W.; McKinney, R. Anne; Multhaup, Gerhard

doi:10.1038/srep15410

Cited by 25 publications

(38 citation statements)

References 78 publications

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“…We have previously shown that a short, 8‐residue Aβ42‐oligomer interacting peptide (AIP) can suppress the aggregation of low‐order Aβ42 oligomers into fibrils in vitro , as well as neutralize Aβ42‐induced neurotoxicity in cell cultures and rat hippocampal slices (Barucker et al . ). We have now used the Drosophila ‘rough eye’ model to investigate the long‐term efficacy of AIP in a full longitudinal study comparing male to female flies.…”

Section: Discussionmentioning

confidence: 97%

“…While the intact mass for D‐AIP (941 m /z ) was still evident at this point, the conversion of intact L‐AIP (941 m /z ) to a smaller metabolite (750 m /z ) appeared to correlate with the loss of the functionally important N‐terminal arginine (Barucker et al . ). Knowing that L‐amino acid peptides typically exhibit decreased biostability compared to D‐amino acid peptides (Tugyi et al .…”

Section: Discussionmentioning

confidence: 97%

“…), can specifically target and neutralize the toxicity of low‐order Aβ42 oligomers (Barucker et al . ). Our 2015 publication showed that the short AIP peptide (RGTFEGKF) was able to rescue Aβ42‐induced neurotoxicity in SH‐SY5Y cells, as well as ameliorate the Aβ42‐induced loss of synaptic spine density and long‐term potentiation (LTP) in organotypic hippocampal slice cultures.…”

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confidence: 97%

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Label‐free distribution of anti‐amyloid D‐AIP in Drosophila melanogaster: prevention of Aβ42‐induced toxicity without side effects in transgenic flies

Zhong

Shobo

Hancock

et al. 2019

Journal of Neurochemistry

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Soluble oligomers of the 42‐amino acid amyloid beta (Aβ42) peptide are highly toxic and suspected as the causative agent of synaptic dysfunction and neuronal loss in Alzheimer's disease (AD). Previously, we have shown that a small, D‐amino acid Aβ42‐oligomer interacting peptide (D‐AIP) can neutralize human Aβ42‐mediated toxicity using in vitro and cell‐based assays. In the present longitudinal study using a transgenic Drosophila melanogaster model, advanced live confocal imaging and mass spectrometry imaging (MALDI‐MSI) showed that the eight amino acid D‐AIP can attenuate Aβ42‐induced toxicity in vivo. By separating male and female flies into distinct groups, the resultant distribution of ingested D‐AIP was different between the sexes. The Aβ42‐induced ‘rough eye’ phenotype could be rescued in the female transgenics, likely because of the co‐localization of D‐AIP with human Aβ42 in the female fly heads. Interestingly, the phenotype could not be rescued in the male transgenics, likely because of the co‐localization of D‐AIP with a confounding male‐specific sex peptide (Acp70A candidate in MSI spectra) in the gut of the male flies. As a novel, more cost‐effective strategy to prevent toxic amyloid formation during the early stages of AD (i.e. neutralization of toxic low‐order Aβ42 oligomers without creating larger aggregates in the process), our longitudinal study establishes that D‐AIP is a stable and highly effective neutralizer of toxic Aβ42 peptides in vivo. Cover Image for this issue: doi: .

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 97%

mentioning

confidence: 97%

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Label‐free distribution of anti‐amyloid D‐AIP in Drosophila melanogaster: prevention of Aβ42‐induced toxicity without side effects in transgenic flies

Zhong

Shobo

Hancock

et al. 2019

Journal of Neurochemistry

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“…They had previously shown that this peptide prevents the fibrillization of Aβ oligomers. In slice culture, they found that AIP prevented a loss of dendritic spines and a decrease in long-term potentiation (LTP) [ 46 ].…”

Section: Slice Culture To Study Prion-like Mechanisms In Alzheimermentioning

confidence: 99%

POSCAbilities: The Application of the Prion Organotypic Slice Culture Assay to Neurodegenerative Disease Research

Pineau

Sim

2020

Biomolecules

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Prion diseases are fatal, transmissible neurodegenerative disorders whose pathogenesis is driven by the misfolding, self-templating and cell-to-cell spread of the prion protein. Other neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and Huntington’s disease, share some of these prion-like features, with different aggregation-prone proteins. Consequently, researchers have begun to apply prion-specific techniques, like the prion organotypic slice culture assay (POSCA), to these disorders. In this review we explore the ways in which the prion phenomenon has been used in organotypic cultures to study neurodegenerative diseases from the perspective of protein aggregation and spreading, strain propagation, the role of glia in pathogenesis, and efficacy of drug treatments. We also present an overview of the advantages and disadvantages of this culture system compared to in vivo and in vitro models and provide suggestions for new directions.

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“…2C). As controls, we used the driver gmr-Gal4 to obtain flies expressing Aβ42 only in the retina, which leads to a 'rough eye' phenotype but does not impair brain function (Costa et al, 2011;Prüßing et al, 2013;Wang et al, 2015;Barucker et al, 2015). Similarly to the data shown in Fig.…”

Section: Knockout Of Sap47 Reduces Lifespanmentioning

confidence: 99%

Implications of the Sap47 null mutation for synapsin phosphorylation, longevity, climbing, and behavioural plasticity in adult Drosophila

Blanco-Redondo

Nuwal

Kneitz

et al. 2019

Journal of Experimental Biology

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The Sap47 gene of Drosophila melanogaster encodes a highly abundant 47 kDa synaptic vesicle-associated protein. Sap47 null mutants show defects in synaptic plasticity and larval olfactory associative learning but the molecular function of Sap47 at the synapse is unknown. We demonstrate that Sap47 modulates the phosphorylation of another highly abundant conserved presynaptic protein, synapsin. Site-specific phosphorylation of Drosophila synapsin has repeatedly been shown to be important for behavioural plasticity but it was not known where these phospho-synapsin isoforms are localized in the brain. Here, we report the distribution of serine-6-phosphorylated synapsin in the adult brain and show that it is highly enriched in rings of synapses in the ellipsoid body and in large synapses near the lateral triangle. The effects of knockout of Sap47 or synapsin on olfactory associative learning/memory support the hypothesis that both proteins operate in the same molecular pathway. We therefore asked if this might also be true for other aspects of their function. We show that knockout of Sap47 but not synapsin reduces lifespan, whereas knockout of Sap47 and synapsin, either individually or together, affects climbing proficiency, as well as plasticity in circadian rhythms and sleep. Furthermore, electrophysiological assessment of synaptic properties at the larval neuromuscular junction (NMJ) reveals increased spontaneous synaptic vesicle fusion and reduced paired pulse facilitation in Sap47 and synapsin single and double mutants. Our results imply that Sap47 and synapsin cooperate non-uniformly in the control of synaptic properties in different behaviourally relevant neuronal networks of the fruitfly.

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Aβ42-oligomer Interacting Peptide (AIP) neutralizes toxic amyloid-β42 species and protects synaptic structure and function

Cited by 25 publications

References 78 publications

Label‐free distribution of anti‐amyloid D‐AIP in Drosophila melanogaster: prevention of Aβ42‐induced toxicity without side effects in transgenic flies

Label‐free distribution of anti‐amyloid D‐AIP in Drosophila melanogaster: prevention of Aβ42‐induced toxicity without side effects in transgenic flies

POSCAbilities: The Application of the Prion Organotypic Slice Culture Assay to Neurodegenerative Disease Research

Implications of the Sap47 null mutation for synapsin phosphorylation, longevity, climbing, and behavioural plasticity in adult Drosophila

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