Substitutions at codon 22 of Alzheimer's A beta peptide induce conformational changes and diverse apoptotic effects in human cerebral endothelial cells

Miravalle, Leticia; Tokuda, Takahiko; Chiarle, Roberto; Giaccone, Giorgio; Bugiani, Orso; Tagliavini, Fabrizio; Frangione, Blas; Ghiso, Jorge

doi:10.1074/jbc.m003154200

Cited by 122 publications

(160 citation statements)

References 47 publications

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“…In the past few years, a number of hypotheses have been put forth to explain how the E22Q mutation affects the refolding process of A␤ in an attempt to rationalize the effect of this mutation on the rate of fibril formation (30)(31)(32). These hypotheses involve (a) a proposed reduction in the ␣-helical structure in the 10-24 N-terminal domain of A␤ accompanying the E22Q mutation (30), (b) an overall increase in ␤-sheet structure in the E22Q A␤ mutant (31), and (c) unfolding of the CHC upon E22Q mutation (33). Hypotheses a and b are not particularly compelling because previous FTIR (34) and more recent NMR (7) studies show little difference in overall secondary structure between the WT and mutated peptide and no dramatic conformational change upon mutation.…”

Section: Discussionmentioning

confidence: 99%

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Baumketner

Krone

Shea³

2008

Proc. Natl. Acad. Sci. U.S.A.

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Amyloid fibrils, large ordered aggregates of amyloid ␤ proteins (A␤), are clinical hallmarks of Alzheimer's disease (AD). The aggregation properties of amyloid ␤ proteins can be strongly affected by singlepoint mutations at positions 22 and 23. The Dutch mutation involves a substitution at position 22 (E22Q) and leads to increased deposition rates of the A␤E22Q peptide onto preseeded fibrils. We investigate the effect of the E22Q mutation on two key regions involved in the folding and aggregation of the A␤ peptide through replica exchange molecular dynamics simulations of the 15-28 fragment of the A␤ peptide. The A␤15-28 peptide encompasses the 22-28 region that constitutes the most structured part of the A␤ peptide (the E22-K28 bend), as well as the central hydrophobic cluster (CHC) (segment 17-21), the primary docking site for A␤ monomers depositing onto fibrils. Our simulations show that the 22-28 bend is preserved in the A␤(15-28) peptide and that the CHC, which is mostly unstructured, interacts with this bend region. The E22Q mutation does not affect the structure of the bend but weakens the interactions between the CHC and the bend. This leads to an increased population of ␤-structure in the CHC. Our analysis of the fibril elongation reaction reveals that the CHC adopts a ␤-strand conformation in the transition state ensemble, and that the E22Q mutation increases aggregation rates by lowering the barrier for A␤ monomer deposition onto a fibril. Thermodynamic signatures of this enhanced fibrillization process from our simulations are in good agreement with experimental observations. Alzheimer's disease ͉ explicit water ͉ familial type ͉ molecular dynamics simulations ͉ replica exchange T he presence of amyloid fibrils in the brain is a clinical hallmark of Alzheimer's disease (AD). The fibrils consist of large ordered aggregates of amyloid-␤ (A␤) peptides, proteolytic by-products of the enzymatic cleavage of the Alzheimer amyloid precursor protein (APP). AD can be sporadic (occurring in elderly patients and characterized by a slow progression) or familial (a hereditary form characterized by early onset of the disease and aggravated severity). The majority of familial forms of AD involve single-point mutations in the 22-23 segment of the A␤ peptide. The focus of this work is on the Dutch form of AD, which involves a mutation encoded by a point substitution G to C at codon 693 of the amyloid precursor protein (APP). The result is the production of an A␤ peptide in which residue E22 is mutated to Q (E22Q mutation). Patients who have this mutation are at risk of developing cerebral amyloid angiopathy that typically leads to cerebral hemorrhage and stroke. Many in vitro experiments show that the A␤E22Q peptide aggregates much more readily than its wild-type (WT) counterpart (1-3). As a free monomer in solution, the WT A␤ peptide is for the most part unstructured with residual structure observed locally in a few regions of the primary sequence (4). The A␤ peptide can populate a variety of oligomeric species, some...

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Section: Discussionmentioning

confidence: 99%

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Baumketner

Krone

Shea³

2008

Proc. Natl. Acad. Sci. U.S.A.

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“…5 Ab , being primarily vasculotropic, is found in the brain vasculature of CAA patients and in experimental models of the disease, whereas Ab 1-42 , endowed with distinct trophism for neurons, predominates in the brain parenchyma of AD patients. [6][7][8][9] Brain vascular degeneration, typical of both sporadic and genetic variants of CAA, is characterized by perivascular deposition of Ab in cortical and leptomeningeal vessels. 9 The hallmark pathological lesion of these diseases is the pervasive dysfunction of brain capillary endothelium.…”

Section: Introductionmentioning

confidence: 99%

FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium

et al. 2006

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Recent evidences suggest that Ab peptides modulate endothelial cell (EC) functions. At low concentrations, Ab 1-40 enhances the pro-angiogenic activity of FGF-2, whereas deposition of excess Ab causes EC dysfunction and cerebral amyloid angiopathy (CAA). We investigated whether FGF-2 attenuates EC dysfunction caused by pathological Ab levels. We studied Ab 1-40 on EC survival, as well as on signals responsible of their angiogenic phenotype. At 5-50 lM Ab 1-40 reduced EC population, caused apoptosis, downregulated FGF-2 production, inhibited FGF-2 binding to heparin, and FGFR1 phosphorylation. Toxic effects were owing to lack of FGF-2 stimulation, as EC overexpressing FGF-2 displayed extraordinary resistance to Ab 1-40 injuries. The FGF-2 mechanism responsible for reversing damages, involves the downstream enhancement of Akt, a pathway independent of eNOS activation.In conclusion, we demonstrate that FGF-2 protects EC from the effects of excess Ab 1-40 , suggesting that it may attenuate the consequences of Ab deposition in pathologies as CAA.

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“…Particularly, we found that the zinc binding can increase the formation probabilities of the b-strand in the central hydrophobic cluster, the salt bridge Asp23-Lys28, and the turn comprising the residues 23-28. These local structures play important roles in the Ab aggregation (179)(180)(181). Therefore, the peptide with zinc binding samples more conformations which are prone to aggregate, suggesting that the metal induced conformational variation is one of the possible mechanisms for metal promoted aggregation of Ab peptide.…”

Section: Metal-coupled Protein Foldingmentioning

confidence: 99%

Protein folding simulations: From coarse‐grained model to all‐atom model

Jian

Wang

et al. 2009

IUBMB Life

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SummaryProtein folding is an important and challenging problem in molecular biology. During the last two decades, molecular dynamics (MD) simulation has proved to be a paramount tool and was widely used to study protein structures, folding kinetics and thermodynamics, and structure-stability-function relationship. It was also used to help engineering and designing new proteins, and to answer even more general questions such as the minimal number of amino acid or the evolution principle of protein families. Nowadays, the MD simulation is still undergoing rapid developments. The first trend is to toward developing new coarse-grained models and studying larger and more complex molecular systems such as protein-protein complex and their assembling process, amyloid related aggregations, and structure and motion of chaperons, motors, channels and virus capsides; the second trend is toward building high resolution models and explore more detailed and accurate pictures of protein folding and the associated processes, such as the coordination bond or disulfide bond involved folding, the polarization, charge transfer and protonate/deprotonate process involved in metal coupled folding, and the ion permeation and its coupling with the kinetics of channels. On these new territories, MD simulations have given many promising results and will continue to offer exciting views. Here, we review several new subjects investigated by using MD simulations as well as the corresponding developments of appropriate protein models. These include but are not limited to the attempt to go beyond the topology based Gō-like model and characterize the energetic factors in protein structures and dynamics, the study of the thermodynamics and kinetics of disulfide bond involved protein folding, the modeling of the interactions between chaperonin and the encapsulated protein and the protein folding under this circumstance, the effort to clarify the important yet still elusive folding mechanism of protein BBL, the development of discrete MD and its application in studying the a-b conformational conversion and oligomer assembling process, and the modeling of metal ion involved protein folding.

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Substitutions at codon 22 of Alzheimer's A beta peptide induce conformational changes and diverse apoptotic effects in human cerebral endothelial cells

Cited by 122 publications

References 47 publications

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

Role of the familial Dutch mutation E22Q in the folding and aggregation of the 15–28 fragment of the Alzheimer amyloid-β protein

FGF-2 overexpression opposes the beta amyloid toxic injuries to the vascular endothelium

Protein folding simulations: From coarse‐grained model to all‐atom model

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