Abstractβ-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673→valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Coincubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.Acentral pathological feature of Alzheimer's disease (AD) is the accumulation of β-Aβ in the form of oligomers and amyloid fibrils in the brain (1). Aβ is generated by sequential cleavage of the APP by β-and γ-secretases and exists as short and long isoforms, Aβ1-40 and Aβ1-42 (2). Aβ1-42 is especially prone to misfolding and builds up aggregates that are thought to be the primary neurotoxic species involved in AD pathogenesis (2,3). AD is usually sporadic, but *To whom correspondence should be addressed. E-mail: ftagliavini@istituto-besta.it. Publisher's Disclaimer: This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS.
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Author ManuscriptScience. Author manuscript; available in PMC 2010 March 13.
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript a small fraction of cases is familial (4). The familial forms show an autosomal dominant pattern of inheritance with virtually complete penetrance and are linked to mutations in the APP, presenilin 1, and presenilin 2 genes (5). The APP mutations close to the sites of β-or γ-secretase cleavage flanking the Aβ sequence overproduce total Aβ or only Aβ1-42, respectively, whereas those that alter amino acids within Aβ result in greater propensity to aggregation in vitro (6, 7).We have identified an APP mutation [Ala 673 →Val 673 (A673V)] that causes disease only in the homozygous state. The mutation consists of a C-to-T transition that results in an alanineto-valine substitution at position 673 (APP770 numbering) corresponding to position 2 of Aβ ( Fig. 1A and fig. S1) (8). The genetic defect was found in a patient with early-onset dementia and in his younger sister, who now shows multiple-domain mild cognitive impairment (MCI) In the patient, the disease presented with behavioral changes and cognitive deficits at the age of 36 years and evolved towar...
Key Points• C elegans specifically recognizes cardiotoxic LCs as toxicants.• This is an innovative model for studying the heart-specific toxicity of amyloidogenic LCs and developing new therapeutic strategies.Poor prognosis and limited therapeutic options characterize immunoglobulin light-chain (AL) amyloidosis with major heart involvement. Reliable experimental models are needed to study light-chain (LC)/heart interactions and to explore strategies for prevention of cardiac damage. We have exploited the nematode Caenorhabditis elegans as a novel tool, because its pharynx is evolutionarily related to the vertebrate heart. Our data demonstrate that the pharyngeal pumping of C elegans is significantly and selectively reduced by LCs from AL patients suffering from cardiomyopathy, but not by amyloid LCs with different organ tropism or nonamyloidogenic LCs from multiple myeloma. This functional alteration is dependent on the LC concentration and results in persistent pharyngeal dysfunction and in a significant reduction of the worms' lifespan. These manifestations are paralleled by an increase of mitochondrial reactive oxygen species and can be prevented by treatment with antioxidant agents. In conclusion, these data indicate that this nematode-based assay is a promising surrogate model for investigating the heart-specific toxicity of amyloidogenic LCs and for a rapid screening of new therapeutic strategies. (Blood. 2014;123(23):3543-3552)
Background: A oligomers are major players in Alzheimer disease, but the tools for their detection are not satisfactory.
Results:We developed a SPR-based immunoassay and a test in C. elegans, specifically identifying toxic oligomers. Conclusion: These methods allow study of the effects of mutations or drugs on A oligomerization. Significance: The SPR-based immunoassay provides new opportunities for the detection of toxic oligomers in biological samples.
Background: A2V mutation is associated with early onset AD-type dementia in homozygous individuals. Results: A2V mutation leads to a peculiar kinetics of A oligomerization. Conclusion: The A N-terminal region plays an important role in the molecular assembly. Significance: in the homozygous condition the A2V mutation led to aggregation, whereas in the heterozygous state the evolution and kinetics of the aggregation process was hindered.
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