Tackling amyloidogenesis in Alzheimer's disease with A2V variants of Amyloid-ß.
Sci Rep
; 6: 20949, 2016 Feb 11.
Article
em En
| MEDLINE
| ID: mdl-26864599
ABSTRACT
We developed a novel therapeutic strategy for Alzheimer's disease (AD) exploiting the properties of a natural variant of Amyloid-ß (Aß) carrying the A2V substitution, which protects heterozygous carriers from AD by its ability to interact with wild-type Aß, hindering conformational changes and assembly thereof. As prototypic compound we designed a six-mer mutated peptide (Aß1-6A2V), linked to the HIV-related TAT protein, which is widely used for brain delivery and cell membrane penetration of drugs. The resulting molecule [Aß1-6A2VTAT(D)] revealed strong anti-amyloidogenic effects in vitro and protected human neuroblastoma cells from Aß toxicity. Preclinical studies in AD mouse models showed that short-term treatment with Aß1-6A2VTAT(D) inhibits Aß aggregation and cerebral amyloid deposition, but a long treatment schedule unexpectedly increases amyloid burden, although preventing cognitive deterioration. Our data support the view that the AßA2V-based strategy can be successfully used for the development of treatments for AD, as suggested by the natural protection against the disease in human A2V heterozygous carriers. The undesirable outcome of the prolonged treatment with Aß1-6A2VTAT(D) was likely due to the TAT intrinsic attitude to increase Aß production, avidly bind amyloid and boost its seeding activity, warning against the use of the TAT carrier in the design of AD therapeutics.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
/
Proteínas Recombinantes de Fusão
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Peptídeos beta-Amiloides
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Fármacos Neuroprotetores
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Produtos do Gene tat do Vírus da Imunodeficiência Humana
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Doença de Alzheimer
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Agregação Patológica de Proteínas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
Sci Rep
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Itália