A Recessive Mutation in the APP Gene with Dominant-Negative Effect on Amyloidogenesis

Abstract

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. NIH Public Access 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...

Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet–Biedl syndrome

“…It is possible that such interactions of mutant proteins exacerbate the disease phenotype but that interaction of mutant and WT protein, although detrimental to WT protein function, does not by itself result in disease. This formulation is consistent with the recent report of a dominant-negative mutation in β-amyloid precursor protein in recessively inherited Alzheimer disease (46).…”

Molecular Mechanisms of Alzheimer Disease Protection by the A673T Allele of Amyloid Precursor Protein

“…Many of these mutations cluster at or near the ␤-or ␥-proteolytic sites, favoring either the overproduction of total amyloid-␤ (A␤) (6 -8) or an increased ratio of the pro-aggregating A␤(1-42) species relative to A␤(1-40) (9 -12). In other instances, mutations within the A␤ peptide promote an increased propensity for aggregation (7,13,14). Together, these genetic findings provide strong support for the amyloid hypothesis of AD, which postulates that an imbalance in the production and clearance of A␤ initiates a cascade of amyloid accumulation, neurotoxicity, and neurodegeneration (15).…”

Crucial role of nonspecific interactions in amyloid nucleation

“…We use the atomistic simulations mainly to justify why, in our coarse-grained model, we choose the following ordering of interaction strengths: e ββ > e sβ > e ss . An additional set of umbrella simulations was performed on the A2V mutation of Aβ42, which is reported to be responsible for early-onset Alzheimer's disease (57), with the purposes of evaluating the relative strengths of interactions for an additional system and further supporting the choice of energy scale in the coarse-grained model. The Aβ42-A2V simulations show the same trend for the interaction strengths as the wild type (WT) with e ββ > e sβ > e ss (14.6, 5.9, and 4:3kT, respectively) (Fig.…”