Dataset Information

Structural dynamics of the ?E22 (Osaka) familial Alzheimer's disease-linked amyloid ?-protein.

ABSTRACT: A familial form of Alzheimer disease recently was described in a kindred in Osaka, Japan. This kindred possesses an amyloid ?-protein (A?) precursor mutation within the A? coding region that results in the deletion of Glu22 (?E22). We report here results of studies of [?E22]A?40 and [?E22]A?42 that sought to elucidate the conformational dynamics, oligomerization behavior, fibril formation kinetics, fibril morphology, and fibril stability of these mutant peptides. Both [?E22]A? peptides had extraordinary ?-sheet formation propensities. The [?E22]A?40 mutant formed ?-sheet secondary structure elements ?400-fold faster. Studies of ?-sheet stability in the presence of fluorinated alcohol cosolvents or high pH revealed that the ?E22 mutation substantially increased stability, producing a rank order of [?E22]A?42 >>A?42 > [?E22]A?40 > A?40. The mutation facilitated formation of oligomers by [?E22]A?42 (dodecamers and octadecamers) that were not observed with A?42. Both A?40 and A?42 peptides formed nebulous globular and small string-like structures immediately upon solvation from lyophilizates, whereas short protofibrillar and fibrillar structures were evident immediately in the ?E22 samples. Determination of the critical concentration for fibril formation for the [?E22]A? peptides showed it to be ?1/2 that of the wild type homologues, demonstrating that the mutations causes a modest increase in fibril stability. The magnitude of this increase, when considered in the context of the extraordinary increase in ?-sheet propensity for the ?E22 peptides, suggests that the primary biophysical effect of the mutation is to accelerate conformational changes in the peptide monomer that facilitate oligomerization and higher-order assembly.

SUBMITTER: Inayathullah M

PROVIDER: S-EPMC3396427 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Structural dynamics of the ΔE22 (Osaka) familial Alzheimer's disease-linked amyloid β-protein.

Inayathullah Mohammed M Teplow David B DB

Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis 20110613 3

A familial form of Alzheimer disease recently was described in a kindred in Osaka, Japan. This kindred possesses an amyloid β-protein (Aβ) precursor mutation within the Aβ coding region that results in the deletion of Glu22 (ΔE22). We report here results of studies of [ΔE22]Aβ40 and [ΔE22]Aβ42 that sought to elucidate the conformational dynamics, oligomerization behavior, fibril formation kinetics, fibril morphology, and fibril stability of these mutant peptides. Both [ΔE22]Aβ peptides had extra ...[more]

PMID: 21668291

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Project description:Mouse models of Alzheimer's disease (AD) show progression through stages reflective of human pathology. Proteomics identification of temporal and sex-linked factors driving AD-related pathways can be used to dissect initiating and propagating events of AD stages to develop biomarkers or design interventions. In the present study, we conducted label-free proteome measurements of mouse hippocampus tissue with variables of time (3, 6, and 9 months), genetic background (5XFAD versus WT), and sex (equal males and females). These time points are associated with well-defined phenotypes with respect to the following: Aβ42 plaque deposition, memory deficits, and neuronal loss, allowing correlation of proteome-based molecular signatures with the mouse model stages. Our data show 5XFAD mice exhibit increases in known human AD biomarkers as amyloid-beta peptide, APOE, GFAP, and ITM2B are upregulated across all time points/stages. At the same time, 23 proteins are here newly associated with Alzheimer's pathology as they are also dysregulated in 5XFAD mice. At a pathways level, the 5XFAD-specific upregulated proteins are significantly enriched for DNA damage and stress-induced senescence at 3-month only, while at 6-month, the AD-specific proteome signature is altered and significantly enriched for membrane trafficking and vesicle-mediated transport protein annotations. By 9-month, AD-specific dysregulation is also characterized by significant neuroinflammation with innate immune system, platelet activation, and hyper-reactive astrocyte-related enrichments. Aside from these temporal changes, analysis of sex-linked differences in proteome signatures uncovered novel sex and AD-associated proteins. Pathway analysis revealed sex-linked differences in the 5XFAD model to be involved in the regulation of well-known human AD-related processes of amyloid fibril formation, wound healing, lysosome biogenesis, and DNA damage. Verification of the discovery results by Western blot and parallel reaction monitoring confirm the fundamental conclusions of the study and poise the 5XFAD model for further use as a molecular tool for understanding AD.

Dataset Information

Structural dynamics of the ?E22 (Osaka) familial Alzheimer's disease-linked amyloid ?-protein.

Publications

Structural dynamics of the ΔE22 (Osaka) familial Alzheimer's disease-linked amyloid β-protein.

Similar Datasets

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