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The A2V mutation as a new tool for hindering A? aggregation: A neutron and x-ray diffraction study.

ABSTRACT: We have described a novel C-to-T mutation in the APP gene that corresponds to an alanine to valine substitution at position 673 in APP (A673V), or position 2 of the amyloid-? (A?) sequence. This mutation is associated with the early onset of AD-type dementia in homozygous individuals, whereas it has a protective effect in the heterozygous state. Correspondingly, we observed differences in the aggregation properties of the wild-type and mutated A? peptides and their mixture. We have carried out neutron diffraction (ND) and x-ray diffraction (XRD) experiments on magnetically-oriented fibers of A?1-28WT and its variant A?1-28A2V. The orientation propensity was higher for A?1-28A2V suggesting that it promotes the formation of fibrillar assemblies. The diffraction patterns by A?1-28WT and A?1-28A2V assemblies differed in shape and position of the equatorial reflections, suggesting that the two peptides adopt distinct lateral packing of the diffracting units. The diffraction patterns from a mixture of the two peptides differed from those of the single components, indicating the presence of structural interference during assembly and orientation. The lowest orientation propensity was observed for a mixture of A?1-28WT and a short N-terminal fragment, A?1-6A2V, which supports a role of A?'s N-terminal domain in amyloid fibril formation.

SUBMITTER: Cantu' L

PROVIDER: S-EPMC5511251 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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The A2V mutation as a new tool for hindering Aβ aggregation: A neutron and x-ray diffraction study.

Cantu' Laura L Colombo Laura L Stoilova Tatiana T Demé Bruno B Inouye Hideyo H Booth Rachel R Rondelli Valeria V Di Fede Giuseppe G Tagliavini Fabrizio F Del Favero Elena E Kirschner Daniel A DA Salmona Mario M

Scientific reports 20170714 1

We have described a novel C-to-T mutation in the APP gene that corresponds to an alanine to valine substitution at position 673 in APP (A673V), or position 2 of the amyloid-β (Aβ) sequence. This mutation is associated with the early onset of AD-type dementia in homozygous individuals, whereas it has a protective effect in the heterozygous state. Correspondingly, we observed differences in the aggregation properties of the wild-type and mutated Aβ peptides and their mixture. We have carried out n ...[more]

PMID: 28710429

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Project description:Alzheimer's disease (AD), the leading cause of dementia in older adults, is a double proteinopathy characterized by amyloid-β (Aβ) and tau pathology. Despite enormous efforts that have been spent in the last decades to find effective therapies, late pharmacological interventions along the course of the disease, inaccurate clinical methodologies in the enrollment of patients, and inadequate biomarkers for evaluating drug efficacy have not allowed the development of an effective therapeutic strategy. The approaches followed so far for developing drugs or antibodies focused solely on targeting Aβ or tau protein. This paper explores the potential therapeutic capacity of an all-D-isomer synthetic peptide limited to the first six amino acids of the N-terminal sequence of the A2V-mutated Aβ, Aβ1-6A2V(D), that was developed following the observation of a clinical case that provided the background for its development. We first performed an in-depth biochemical characterization documenting the capacity of Aβ1-6A2V(D) to interfere with the aggregation and stability of tau protein. To tackle Aβ1-6A2V(D) in vivo effects against a neurological decline in genetically predisposed or acquired high AD risk mice, we tested its effects in triple transgenic animals harboring human PS1(M146 V), APP(SW), and MAPT(P301L) transgenes and aged wild-type mice exposed to experimental traumatic brain injury (TBI), a recognized risk factor for AD. We found that Aβ1-6A2V(D) treatment in TBI mice improved neurological outcomes and reduced blood markers of axonal damage. Exploiting the C. elegans model as a biosensor of amyloidogenic proteins' toxicity, we observed a rescue of locomotor defects in nematodes exposed to the brain homogenates from TBI mice treated with Aβ1-6A2V(D) compared to TBI controls. By this integrated approach, we demonstrate that Aβ1-6A2V(D) not only impedes tau aggregation but also favors its degradation by tissue proteases, confirming that this peptide interferes with both Aβ and tau aggregation propensity and proteotoxicity.

Dataset Information

The A2V mutation as a new tool for hindering A? aggregation: A neutron and x-ray diffraction study.

Publications

The A2V mutation as a new tool for hindering Aβ aggregation: A neutron and x-ray diffraction study.

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