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Neurobiol Dis. 2014 Feb;62:521-32. doi: 10.1016/j.nbd.2013.10.024. Epub 2013 Nov 1.

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

Author information

1
Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy. Electronic address: luisa.diomede@marionegri.it.
2
Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.
3
Department of Molecular Biochemistry and Pharmacology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
4
Department of Environmental Health Sciences, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.
5
Proteomics Unit, IRCCS "Centro S. Giovanni di Dio-Fatebenefratelli", Via Pilastroni 4, 25125 Brescia, Italy.
6
Department of Cardiovascular Research, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Via La Masa 19, 20156 Milan, Italy.

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 β-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 β (Aβ) production and aggregation; heterozygous carriers remain unaffected. It is not clear how misfolding and aggregation of Aβ 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 Aβ protein are currently available. Using the invertebrate Caenorhabditis elegans, we generated the first transgenic animal model to express the human Aβ1-40 wild-type (WT) in neurons or possess the A2V mutation (Aβ1-40A2V). Insertion of an Aβ-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 Aβ1-40WT. The expression of both WT and A2V Aβ1-40 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.

KEYWORDS:

A673V mutation; Alzheimer's disease; Amyloid β peptides; Caenorhabditis elegans; Toxic oligomers

PMID:
24184799
PMCID:
PMC4068289
DOI:
10.1016/j.nbd.2013.10.024
[Indexed for MEDLINE]
Free PMC Article
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