Abstract
We have described a novel C-to-T mutation in the APP gene that corresponds to an alanine to valine substitution at position 673 in APP (A673V), or position 2 of the amyloid-β (Aβ) sequence. This mutation is associated with the early onset of AD-type dementia in homozygous individuals, whereas it has a protective effect in the heterozygous state. Correspondingly, we observed differences in the aggregation properties of the wild-type and mutated Aβ peptides and their mixture. We have carried out neutron diffraction (ND) and x-ray diffraction (XRD) experiments on magnetically-oriented fibers of Aβ1-28WT and its variant Aβ1-28A2V. The orientation propensity was higher for Aβ1-28A2V suggesting that it promotes the formation of fibrillar assemblies. The diffraction patterns by Aβ1-28WT and Aβ1-28A2V assemblies differed in shape and position of the equatorial reflections, suggesting that the two peptides adopt distinct lateral packing of the diffracting units. The diffraction patterns from a mixture of the two peptides differed from those of the single components, indicating the presence of structural interference during assembly and orientation. The lowest orientation propensity was observed for a mixture of Aβ1-28WT and a short N-terminal fragment, Aβ1-6A2V, which supports a role of Aβ’s N-terminal domain in amyloid fibril formation.
Highlights
Alzheimer’s disease (AD), the most frequent form of dementia in the elderly, is defined neuropathologically by extracellular amyloid plaques and intraneuronal neurofibrillary tangles in limbic and cortical regions of brain[1]
In vitro studies with fibroblasts from patients and controls, amyloid β precursor protein (APP) transfected cells and synthetic Aβ peptides show that the A673V APP mutation has two pathogenic effects: (i) shifting APP processing toward the amyloidogenic pathway with increased Aβ production, and (ii) enhancing the aggregation and fibrillogenic properties of Aβ
Understanding the molecular basis of AD heterogeneity may help design more appropriate therapies based on recognition of different target phenotypes
Summary
Alzheimer’s disease (AD), the most frequent form of dementia in the elderly, is defined neuropathologically by extracellular amyloid plaques and intraneuronal neurofibrillary tangles in limbic and cortical regions of brain[1]. Aggregated Aβ species are believed to trigger a cascade of events that lead to protein tau hyperphosphorylation, misfolding, and assembly into abnormal filaments of neurofibrillary tangles, disruption of the neuronal cytoskeleton, widespread synaptic loss, and neurodegeneration[6, 7] This cascade appears to offer a number of points at which to interfere with the sequence of pathology; to date all strategies have faced serious hurdles in clinical application, where the tested drugs have been ineffective or caused severe adverse events[8, 9]. The labile structure of the mutated hexapeptide may facilitate heterotypic interaction with Aβ, thereby hindering Aβ assembly These preliminary experiments offered a proof of concept and provide a foundation for the rational design of therapeutic agents based on Aβ fragments with the A2V mutation and peptido-mimetic molecules retaining the key functional properties of the mutated Aβ. In light of these observations the main questions still to be answered are: (i) the structural characterization of macromolecular assemblies of Aβ peptides with the A2V mutation, and (ii) the biochemical basis for the aggressiveness of the A2V mutation
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