Expression of A2V-mutated Aß in Caenorhabditis elegans results in oligomer formation and toxicity.
Neurobiol Dis
; 62: 521-32, 2014 Feb.
Article
em En
| MEDLINE
| ID: mdl-24184799
ABSTRACT
Although Alzheimer's disease (AD) is usually sporadic, in a small proportion of cases it is familial and can be linked to mutations in ß-amyloid precursor protein (APP). Unlike the other genetic defects, the mutation [alanine-673âvaline-673] (A673V) causes the disease only in the homozygous condition with enhanced amyloid ß (Aß) production and aggregation; heterozygous carriers remain unaffected. It is not clear how misfolding and aggregation of Aß is affected in vivo by this mutation and whether this correlates with its toxic effects. No animal models over-expressing the A673V-APP gene or alanine-2-valine (A2V) mutated human Aß protein are currently available. Using the invertebrate Caenorhabditis elegans, we generated the first transgenic animal model to express the human Aß1-40 wild-type (WT) in neurons or possess the A2V mutation (Aß1-40A2V). Insertion of an Aß-mutated gene into this nematode reproduced the homozygous state of the human pathology. Functional and biochemical characteristics found in the A2V strain were compared to those of transgenic C. elegans expressing Aß1-40WT. The expression of both WT and A2V Aß1-40 specifically reduced the nematode's lifespan, causing behavioral defects and neurotransmission impairment which were worse in A2V worms. Mutant animals were more resistant than WT to paralysis induced by the cholinergic agonist levamisole, indicating that the locomotor defect was specifically linked to postsynaptic dysfunctions. The toxicity caused by the mutated protein was associated with a high propensity to form oligomeric assemblies which accumulate in the neurons, suggesting this to be the central event involved in the postsynaptic damage and early onset of the disease in homozygous human A673V carriers.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fragmentos de Peptídeos
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Peptídeos beta-Amiloides
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Neurônios
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Neurobiol Dis
Assunto da revista:
NEUROLOGIA
Ano de publicação:
2014
Tipo de documento:
Article