Short Aβ peptides attenuate Aβ42 toxicity in vivo

Moore, Brenda D.; Martin, Jason; Mena, Lorena de; Sánchez, Jonatan; Cruz, Pedro; Ceballos‐Diaz, Carolina; Ladd, Thomas B.; Ran, Yong; Levites, Yona; Kukar, Thomas; Kurian, Justin; McKenna, Robert; Koo, Edward H.; Borchelt, David R.; Janus, Christopher; Rincón-Limas, Diego E.; Fernández-Fúnez, Pedro; Golde, Todd E.

doi:10.1084/jem.20170600

Cited by 69 publications

(72 citation statements)

References 69 publications

(92 reference statements)

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“…4A). In contrast, and consistent with our previous observations [44], a single copy of the Aβ42 WT induced a more aggressive phenotype characterized by disorganization, ommatidial fusion and partial lack of bristles (Fig. 4A).…”

Section: Neurotoxic Assessment Of Mutant Aβ Peptides In the Drosophilsupporting

confidence: 93%

Aß40 mutants protect Drosophila against Aß42 toxicity despite their amyloidogenic properties in the non-transgenic mouse brain

Mena¹,

Smith²,

Martin³

et al. 2020

Preprint

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BackgroundSelf-assembly of the amyloid-β (Aβ) peptide into aggregates, from small oligomers to amyloid fibrils, is fundamentally linked with Alzheimer’s disease (AD). However it is clear that not all forms of Aβ are equally harmful, and that linking a specific aggregate to toxicity also depends on the assays and model systems used [1, 2]. Though a central postulate of the amyloid cascade hypothesis, there remain many gaps in our understanding regarding the links between Aβ deposition and neurodegeneration.MethodsIn this study, we examined familial mutations of Aβ that increase aggregation and oligomerization, E22G and DE22, and induce cerebral amyloid angiopathy, E22Q and D23N. We also investigated synthetic mutations that stabilize dimerization, S26C, and a phospho-mimetic, S8E, and non-phospho-mimetic, S8A. To that end, we utilized BRI2-Aβ fusion technology and rAAV2/1 based somatic brain transgenesis in mice to selectively express individual mutant Aβ species in vivo . In parallel we generated PhiC31-based transgenic Drosophila melanogaster expressing wild type (WT) and Aβ40 and Aβ42 mutants, fused to the Argos signal peptide to assess the extent of Aβ42-induced toxicity as well as to interrogate the combined effect of different Aβ40 and Aβ42 species.ResultsWhen expressed in the mouse brain for 6 months, Aβ42 E22G, Aβ42 E22Q/D23N, and Aβ42WT formed amyloid aggregates consisting of some diffuse material as well as cored plaques, whereas other mutants formed predominantly diffuse amyloid deposits. Moreover, while Aβ40WT showed no distinctive phenotype, Aβ40 E22G and E22Q/D23N formed unique aggregates that accumulated in mouse brains. This is the first evidence that mutant Aβ40 overexpression leads to deposition under certain conditions. Interestingly, we found that mutant Aβ42 E22G, E22Q, and S26C, but not Aβ40, were toxic to the eye of Drosophila . In contrast, flies expressing a copy of Aβ40 (WT or mutants) in addition to Aβ42WT, showed improved phenotypes, suggesting possible protective qualities for Aβ40.ConclusionsThese studies suggest that some Aβ40 mutants form unique amyloid aggregates in mouse brains, despite protecting against Aβ42 toxicity in Drosophila , which highlights the significance of using different systems for a better understanding of AD pathogenicity and more accurate screening for new potential therapies.

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Section: Neurotoxic Assessment Of Mutant Aβ Peptides In the Drosophilsupporting

confidence: 93%

Aß40 mutants protect Drosophila against Aß42 toxicity despite their amyloidogenic properties in the non-transgenic mouse brain

Mena¹,

Smith²,

Martin³

et al. 2020

Preprint

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“…These peptides have 3 different specific amino acids that could modify the human peptides ability to form toxic aggregates or oligomers. Different combinations of Aβ peptides are known to interfere with the rate of formation of aggregates/oligomers as well as their structural type [71]. This is consistent with the possibility that shorter Aβ40 peptides (or sequence divergent rodent peptides) could prevent toxicity of Aβ42 in rodent models.…”

Section: Discussionsupporting

confidence: 61%

A human embryonic stem cell model of Aβ-dependent chronic progressive neurodegeneration

Ubina

Magallanes

Srivastava

et al. 2018

Preprint

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32 We describe construction and phenotypic analysis of a human embryonic stem cell model of 33 progressive A-dependent neurodegeneration (ND) with potential relevance to Alzheimer's 34 disease (AD). We modified one allele of the normal APP locus to directly express a secretory 35 form of A40 or A42, eliminating the need for amyloidogenic APP proteolysis. Following 36 neuronal differentiation edited cell lines specifically accumulate aggregated/oligomeric A, 37 exhibit a synaptic deficit and have an abnormal accumulation of endolysosomal vesicles. Edited 38 cultures progress to a stage of overt ND. All phenotypes appear at earlier culture times for A42 39 relative to A40. Whole transcriptome RNA-Seq analysis identified 23 up and 70 down 40 regulated genes (DEGs) with similar directional fold change but larger absolute values in the 41 A42 samples suggesting common underlying pathogenic mechanisms. Pathway/annotation 42 analysis suggested that down regulation of extracellular matrix and cilia functions are 43 significantly overrepresented. This cellular model could be useful for uncovering mechanisms 44 directly linking A to neuronal death and as a tool to screen for new therapeutic agents that slow 45 or prevent human ND. Introduction47 Alzheimer's disease (AD) is a chronic progressive neurodegenerative disorder with a decade's 48 long preclinical phase. Clinical features include memory loss accompanied by progressive 49 cognitive dysfunction, cortical atrophy and ultimately death. Neuropathology is well defined by 50 a widespread accumulation of two prominent lesions in cortical brain regions: amyloid plaques 51 and neurofibrillary tangles. Plaques are composed primarily of higher-ordered aggregates of 52 small A peptides derived from amyloidogenic proteolysis of a large transmembrane amyloid 53 precursor protein (APP). Tangles are composed largely of hyperphosphorylated aggregates of a 54 microtubule stabilizing protein tau, a product of the MAPT gene. All forms of AD exhibit 55 accumulation of both A plaques and neurofibrillary tangles and both are considered necessary 56 for a definitive postmortem diagnosis [1]. Both plaque and tangle neuropathology correlate with 57 decrements in cognitive function in AD, but our mechanistic understanding of how these lesions 58 contribute to progressive neurodegeneration (ND) is still incomplete [2]. The reasons for this 59 include the inherent complexity of the disease as well as inadequacies of current animal and 60 cellular experimental models. 61 There are two general forms of AD: a rare autosomal dominant familial form (FAD) and the 62 more prevalent sporadic form (SAD). Both FAD and SAD have a complex genetic component 63 (i.e. >20 identified risk alleles with APOE4 being the most prominent), significant life-style 64 associations (obesity, sleep, exercise, etc.), several associated co-morbidities (i.e. diabetes, head 65 trauma), and of course the most important correlate of all, old age. This complexity coupled with 66 the lengthy time course of the disea...

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“…Interestingly, overexpression of the phosphomimetic Ab42 S8E resulted in sparse deposits, with very low levels of both SDS-soluble and FA-soluble Ab42, whereas nonphospho-mimetic Ab42 S8A exhibited increased deposits, suggesting that phosphorylation does not play a signi cant role in Ab42 deposition. We have previously shown that overexpression of WT Aβ40 resulted in no amyloid pathology [44]. However, when a series of BRI2-Aβ40 mutants were overexpressed in the neonatal brain, we observed that Aβ40 E22G and E22Q/D23N aggregated and accumulated in the brain (Fig.…”

Section: Resultsmentioning

confidence: 75%

Aß40 displays amyloidogenic properties in the non-transgenic mouse brain but does not exacerbate Aß42 toxicity in Drosophila.

Mena¹,

Smith²,

Martín³

et al. 2020

Preprint

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Background Self-assembly of the amyloid-β (Aβ) peptide into aggregates, from small oligomers to amyloid fibrils, is fundamentally linked with Alzheimer’s disease (AD). However it is clear that not all forms of Aβ are equally harmful, and that linking a specific aggregate to toxicity also depends on the assays and model systems used [1, 2]. Though a central postulate of the amyloid cascade hypothesis, there remain many gaps in our understanding regarding the links between Aβ deposition and neurodegeneration. Methods In this study, we examined familial mutations of Aβ that increase aggregation and oligomerization, E22G and DE22, and induce cerebral amyloid angiopathy, E22Q and D23N. We also investigated synthetic mutations that stabilize dimerization, S26C, and a phospho-mimetic, S8E, and non-phospho-mimetic, S8A. To that end, we utilized BRI2-Aβ fusion technology and rAAV2/1 based somatic brain transgenesis in mice to selectively express individual mutant Aβ species in vivo. In parallel we generated PhiC31-based transgenic Drosophila melanogaster expressing wild type (WT) and Aβ40 and Aβ42 mutants, fused to the Argos signal peptide to assess the extent of Aβ42-induced toxicity as well as to interrogate the combined effect of different Aβ40 and Aβ42 species.Results When expressed in the mouse brain for 6 months, Aβ42 E22G, Aβ42 E22Q/D23N, and Aβ42WT formed amyloid aggregates consisting of some diffuse material as well as cored plaques, whereas other mutants formed predominantly diffuse amyloid deposits. Moreover, while Aβ40WT showed no distinctive phenotype, Aβ40 E22G and E22Q/D23N formed unique aggregates that accumulated in mouse brains. This is the first evidence that mutant Aβ40 overexpression leads to deposition under certain conditions. Interestingly, we found that mutant Aβ42 E22G, E22Q, and S26C, but not Aβ40, were toxic to the eye of Drosophila. In contrast, flies expressing a copy of Aβ40 (WT or mutants) in addition to Aβ42WT, showed improved phenotypes, suggesting possible protective qualities for Aβ40. Conclusions These studies suggest that while some Aβ40 mutants form unique amyloid aggregates in mouse brains, they do not exacerbate Aβ42 toxicity in Drosophila, which highlights the significance of using different systems for a better understanding of AD pathogenicity and more accurate screening for new potential therapies.

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Short Aβ peptides attenuate Aβ42 toxicity in vivo

Cited by 69 publications

References 69 publications

Aß40 mutants protect Drosophila against Aß42 toxicity despite their amyloidogenic properties in the non-transgenic mouse brain

Aß40 mutants protect Drosophila against Aß42 toxicity despite their amyloidogenic properties in the non-transgenic mouse brain

A human embryonic stem cell model of Aβ-dependent chronic progressive neurodegeneration

Aß40 displays amyloidogenic properties in the non-transgenic mouse brain but does not exacerbate Aß42 toxicity in Drosophila.

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