Expression of A2V-mutated Aβ in Caenorhabditis elegans results in oligomer formation and toxicity

NEUROBIOLOGY OF DISEASE

卷:62

Article

Diomede, Luisa¹  Di Fede, Giuseppe²  Romeo, Margherita¹  Bagnati, Renzo³  Ghidoni, Roberta⁴  Fiordaliso, Fabio⁵  Rossi, Alessandro¹  Paterlini, Anna⁴  Benussi, Luisa⁴  Bastone, Antonio¹  Stravalaci, Matteo¹  Gobbi, Marco¹  Tagliavini, Fabrizio²  Salmona, Mario¹ 

[1] IRCCS Ist Ric Farmacol Mario Negri, Dept Mol Biochem & Pharmacol, I-20156 Milan, Italy

[2] Ist Nazl Neurol Carlo Besta, Div Neurol & Neuropathol, I-20133 Milan, Italy

[3] IRCCS Ist Ric Farmacol Mario Negri, Dept Environm Hlth Sci, I-20156 Milan, Italy

[4] IRCCS Ctr S Giovanni Dio Fatebenefratelli, Prote Unit, I-25125 Brescia, Italy

[5] IRCCS Ist Ric Farmacol Mario Negri, Dept Cardiovasc Res, I-20156 Milan, Italy

关键词: Alzheimer's disease;    Amyloid beta peptides;    Toxic oligomers;    Caenorhabditis elegans;    A673V mutation;   

DOI  :  10.1016/j.nbd.2013.10.024

来源: Elsevier

【 摘 要 】

Although Alzheimer's disease (AD) is usually sporadic, in a small proportion of cases it is familial and can be linked to mutations in beta-amyloid precursor protein (APP). Unlike the other genetic defects, the mutation [alanine-673 -> valine-673] (A673V) causes the disease only in the homozygous condition with enhanced amyloid p (A beta) production and aggregation; heterozygous carriers remain unaffected. It is not clear how misfolding and aggregation of A beta 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 A beta protein are currently available. Using the invertebrate Caenorhabditis elegans, we generated the first transgenic animal model to express the human A beta(1-40) wild-type (WT) in neurons or possess the A2V mutation (A beta(1-40A2V)) Insertion of an A beta-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 A beta(1-40WT). The expression of both WT and A2VA beta(1-40) 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. (C) 2013 The Authors. Published by Elsevier Inc All rights reserved.

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