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Familial Alzheimer's disease Osaka mutant (?E22) ?-barrels suggest an explanation for the different A?1-40/42 preferred conformational states observed by experiment.

ABSTRACT: An unusual ?E693 mutation in the amyloid precursor protein (APP) producing a ?-amyloid (A?) peptide lacking glutamic acid at position 22 (Glu22) was recently discovered, and dabbed the Osaka mutant (?E22). Previously, several point mutations in the A? peptide involving Glu22 substitutions were identified and implicated in the early onset of familial Alzheimer's disease (FAD). Despite the absence of Glu22, the Osaka mutant is also associated with FAD, showing a recessive inheritance in families affected by the disease. To see whether this aggregation-prone A? mutant could directly relate to the A? ion channel-mediated mechanism as observed for the wild type (WT) A? peptide in AD pathology, we modeled Osaka mutant ?-barrels in a lipid bilayer. Using molecular dynamics (MD) simulations, two conformer ?E22 barrels with the U-shaped monomer conformation derived from NMR-based WT A? fibrils were simulated in explicit lipid environment. Here, we show that the ?E22 barrels obtain the lipid-relaxed ?-sheet channel topology, indistinguishable from the WT A?1-42 barrels, as do the outer and pore dimensions of octadecameric (18-mer) ?E22 barrels. Although the ?E22 barrels lose the cationic binding site in the pore which is normally provided by the negatively charged Glu22 side chains, the mutant pores gain a new cationic binding site by Glu11 at the lower bilayer leaflet, and exhibit ion fluctuations similar to the WT barrels. Of particular interest, this deletion mutant suggests that toxic WT A?1-42 would preferentially adopt a less C-terminal turn similar to that observed for A?17-42, and explains why the solid state NMR data for A?1-40 point to a more C-terminal turn conformation. The observed ?E22 barrels conformational preferences also suggest an explanation for the lower neurotoxicity in rat primary neurons as compared to WT A?1-42.

SUBMITTER: Jang H

PROVIDER: S-EPMC3946471 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Familial Alzheimer's disease Osaka mutant (ΔE22) β-barrels suggest an explanation for the different Aβ1-40/42 preferred conformational states observed by experiment.

Jang Hyunbum H Arce Fernando Teran FT Ramachandran Srinivasan S Kagan Bruce L BL Lal Ratnesh R Nussinov Ruth R

The journal of physical chemistry. B 20130913 39

An unusual ΔE693 mutation in the amyloid precursor protein (APP) producing a β-amyloid (Aβ) peptide lacking glutamic acid at position 22 (Glu22) was recently discovered, and dabbed the Osaka mutant (ΔE22). Previously, several point mutations in the Aβ peptide involving Glu22 substitutions were identified and implicated in the early onset of familial Alzheimer's disease (FAD). Despite the absence of Glu22, the Osaka mutant is also associated with FAD, showing a recessive inheritance in families a ...[more]

PMID: 24000923

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Project description:The ?E693 (Japanese) mutation of the ?-amyloid precursor protein leads to production of ?E22-A? peptides such as ?E22-A?(1-39). Despite reports that these peptides do not form fibrils, here we show that, on the contrary, the peptide forms fibrils essentially instantaneously. The fibrils are typical amyloid fibrils in all respects except that they cause only low levels of thioflavin T (ThT) fluorescence, which, however, develops with no lag phase. The fibrils bind ThT, but with a lower affinity and a smaller number of binding sites than wild-type (WT) A?(1-40). Fluorescence depolarization confirms extremely rapid aggregation of ?E22-A?(1-39). Size exclusion chromatography (SEC) indicates very low concentrations of soluble monomer and oligomer, but only in the presence of some organic solvent, e.g., 2% (v/v) DMSO. The critical concentration is approximately 1 order of magnitude lower for ?E22-A?(1-39) than for WT A?(1-40). Several lines of evidence point to an altered structure for ?E22-A?(1-39) compared to that of WT A?(1-40) fibrils. In addition to differences in ThT binding and fluorescence, PITHIRDS-CT solid-state nuclear magnetic resonance (NMR) measurements of ?E22-A?(1-39) are not compatible with the parallel in-register ?-sheet generally observed for WT A?(1-40) fibrils. X-ray fibril diffraction showed different D spacings: 4.7 and 10.4 Å for WT A?(1-40) and 4.7 and 9.6 Å for ?E22-A?(1-39). Equimolar mixtures of ?E22-A?(1-39) and WT A?(1-40) also produced fibrils extremely rapidly, and by the criteria of ThT fluorescence and electron microscopic appearance, they were the same as fibrils made from pure ?E22-A?(1-39). X-ray diffraction of fibrils formed from 1:1 molar mixtures of ?E22-A?(1-39) and WT A?(1-40) showed the same D spacings as fibrils of the pure mutant peptide, not the wild-type peptide. These findings are consistent with extremely rapid nucleation by ?E22-A?(1-39), followed by fibril extension by WT A?(1-40), and "conversion" of the wild-type peptide to a structure similar to that of the mutant peptide, in a manner reminiscent of the prion conversion phenomenon.

Project description:ObjectiveThe diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) must be improved before widespread clinical use. This study aimed to determine whether CSF A?42/A?40 and A?42/A?38 ratios are better diagnostic biomarkers of AD during both predementia and dementia stages in comparison to CSF A?42 alone.MethodsThe study comprised three different cohorts (n = 1182) in whom CSF levels of A?42, A?40, and A?38 were assessed. CSF A?s were quantified using three different immunoassays (Euroimmun, Meso Scale Discovery, Quanterix). As reference standard, we used either amyloid ((18)F-flutemetamol) positron emission tomography (PET) imaging (n = 215) or clinical diagnosis (n = 967) of well-characterized patients.ResultsWhen using three different immunoassays in cases with subjective cognitive decline and mild cognitive impairment, the CSF A?42/A?40 and A?42/A?38 ratios were significantly better predictors of abnormal amyloid PET than CSF A?42. Lower A?42, A?42/A?40, and A?42/A?38 ratios, but not A?40 and A?38, correlated with smaller hippocampal volumes measured by magnetic resonance imaging. However, lower A?38, A?40, and A?42, but not the ratios, correlated with non-AD-specific subcortical changes, that is, larger lateral ventricles and white matter lesions. Further, the A?42/A?40 and A?42/A?38 ratios showed increased accuracy compared to A?42 when distinguishing AD from dementia with Lewy bodies or Parkinson's disease dementia and subcortical vascular dementia, where all A?s (including A?42) were decreased.InterpretationThe CSF A?42/A?40 and A?42/A?38 ratios are significantly better than CSF A?42 to detect brain amyloid deposition in prodromal AD and to differentiate AD dementia from non-AD dementias. The ratios reflect AD-type pathology better, whereas decline in CSF A?42 is also associated with non-AD subcortical pathologies. These findings strongly suggest that the ratios rather than CSF A?42 should be used in the clinical work-up of AD.

Dataset Information

Familial Alzheimer's disease Osaka mutant (?E22) ?-barrels suggest an explanation for the different A?1-40/42 preferred conformational states observed by experiment.

Publications

Familial Alzheimer's disease Osaka mutant (ΔE22) β-barrels suggest an explanation for the different Aβ1-40/42 preferred conformational states observed by experiment.

Similar Datasets

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