The Alzheimer Disease Protective Mutation A2T Modulates Kinetic and Thermodynamic Properties of Amyloid-β (Aβ) Aggregation

Benilova, Iryna; Gallardo, Rodrigo; Ungureanu, Andreea Alexandra; Cano, Virginia Castillo; An, Shengli; Ramakers, Meine; Bartic, Carmen; Rousseau, Frédéric; Schymkowitz, Joost; Strooper, Bart De

doi:10.1074/jbc.m114.599027

Cited by 140 publications

(175 citation statements)

References 46 publications

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“…Thus, if started early enough, lowering Aβ levels could be sufficient to slow down the disease process in Alzheimer's disease. This idea is further supported by the genetic finding indicating that a naturally occurring A673T rare variant in APP protects from Alzheimer's-disease-and age-related cognitive decline by reducing BACE1-mediated cleavage of APP and/or producing less of the aggregation-prone Aβ40 containing the A→T variation at position 2 (Di Fede et al, 2009;Jonsson et al, 2012;Benilova et al, 2014;Das et al, 2016). Soluble Aβ42 dimers extracted from the Alzheimer's disease brain have been shown to specifically increase the phosphorylation of tau and subsequently promote neurodegeneration, supporting the intimate link between Aβ and tau in Alzheimer's disease pathogenesis (Shankar et al, 2008).…”

Section: Introductionsupporting

confidence: 54%

SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

Kurkinen

Marttinen

Turner

et al. 2016

Journal of Cell Science

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Dysfunction and loss of synapses are early pathogenic events in Alzheimer's disease. A central step in the generation of toxic amyloid-β (Aβ) peptides is the cleavage of amyloid precursor protein (APP) by β-site APP-cleaving enzyme (BACE1). Here, we have elucidated whether downregulation of septin (SEPT) protein family members, which are implicated in synaptic plasticity and vesicular trafficking, affects APP processing and Aβ generation. SEPT8 was found to reduce soluble APPβ and Aβ levels in neuronal cells through a posttranslational mechanism leading to decreased levels of BACE1 protein. In the human temporal cortex, we identified alterations in the expression of specific SEPT8 transcript variants in a manner that correlated with Alzheimer's-disease-related neurofibrillary pathology. These changes were associated with altered β-secretase activity. We also discovered that the overexpression of a specific Alzheimer'sdisease-associated SEPT8 transcript variant increased the levels of BACE1 and Aβ peptides in neuronal cells. These changes were related to an increased half-life of BACE1 and the localization of BACE1 in recycling endosomes. These data suggest that SEPT8 modulates β-amyloidogenic processing of APP through a mechanism affecting the intracellular sorting and accumulation of BACE1.

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Section: Introductionsupporting

confidence: 54%

SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

Kurkinen

Marttinen

Turner

et al. 2016

Journal of Cell Science

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“…However, the chemical shifts of the unstructured N-terminal region up to G9 are drastically different. It was previously reported that the soluble N-terminus is not in the rigid fibril core (56,57), but plays a central role in enhancing b-sheet formation and stabilizing amyloid fibrils (58)(59)(60), especially at low pH (61). The N-terminal region might support the aggregation-prone sequence stabilizing b-sheet formation as described by Abedini and Raleigh (50,51).…”

Section: The Very N-terminus Of Ab Affects Its Fibrillization Kineticsmentioning

confidence: 99%

Pyroglutamate-Modified Amyloid-β(3–42) Shows α-Helical Intermediates before Amyloid Formation

Dammers

Reiß

Gremer

et al. 2017

Biophysical Journal

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Pyroglutamate-modified amyloid-b (pEAb) has been described as a relevant Ab species in Alzheimer's-diseaseaffected brains, with pEAb (3-42) as a dominant isoform. Ab (1-40) and Ab (1-42) have been well characterized under various solution conditions, including aqueous solutions containing trifluoroethanol (TFE). To characterize structural properties of pEAb (3-42) possibly underlying its drastically increased aggregation propensity compared to Ab (1-42), we started our studies in various TFE-water mixtures and found striking differences between the two Ab species. Soluble pEAb (3-42) has an increased tendency to form b-sheet-rich structures compared to Ab (1-42), as indicated by circular dichroism spectroscopy data. Kinetic assays monitored by thioflavin-T show drastically accelerated aggregation leading to large fibrils visualized by electron microscopy of pEAb (3-42) in contrast to Ab (1-42). NMR spectroscopy was performed for backbone and side-chain chemical-shift assignments of monomeric pEAb (3-42) in 40% TFE solution. Although the difference between pEAb (3-42) and Ab (1-42) is purely N-terminal, it has a significant impact on the chemical environment of >20% of the total amino acid residues, as revealed by their NMR chemical-shift differences. Freshly dissolved pEAb (3-42) contains two a-helical regions connected by a flexible linker, whereas the N-terminus remains unstructured. We found that these a-helices act as a transient intermediate to b-sheet and fibril formation of pEAb (3-42).

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“…Two recent studies that employed thioflavin T (ThT) fluorescence monitoring suggest very different effects of the A2T mutation on Ab 1-42 aggregation (42,43). Benilova et al showed no change in Ab 1-42 aggregation upon either A2T or A2V mutation (43).…”

Section: Introductionmentioning

confidence: 98%

Alzheimer’s Protective A2T Mutation Changes the Conformational Landscape of the Aβ1–42 Monomer Differently Than Does the A2V Mutation

Das

Murray

Belfort

2015

Biophysical Journal

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The aggregation of amyloid-β (Aβ) peptides plays a crucial role in the etiology of Alzheimer's disease (AD). Recently, it has been reported that an A2T mutation in Aβ can protect against AD. Interestingly, a nonpolar A2V mutation also has been found to offer protection against AD in the heterozygous state, although it causes early-onset AD in homozygous carriers. Since the conformational landscape of the Aβ monomer is known to directly contribute to the early-stage aggregation mechanism, it is important to characterize the effects of the A2T and A2V mutations on Aβ₁₋₄₂ monomer structure. Here, we have performed extensive atomistic replica-exchange molecular dynamics simulations of the solvated wild-type (WT), A2V, and A2T Aβ₁₋₄₂ monomers. Our simulations reveal that although all three variants remain as collapsed coils in solution, there exist significant structural differences among them at shorter timescales. A2V exhibits an enhanced double-hairpin population in comparison to the WT, similar to those reported in toxic WT Aβ₁₋₄₂ oligomers. Such double-hairpin formation is caused by hydrophobic clustering between the N-terminus and the central and C-terminal hydrophobic patches. In contrast, the A2T mutation causes the N-terminus to engage in unusual electrostatic interactions with distant residues, such as K16 and E22, resulting in a unique population comprising only the C-terminal hairpin. These findings imply that a single A2X (where X = V or T) mutation in the primarily disordered N-terminus of the Aβ₁₋₄₂ monomer can dramatically alter the β-hairpin population and switch the equilibrium toward alternative structures. The atomistically detailed, comparative view of the structural landscapes of A2V and A2T variant monomers obtained in this study can enhance our understanding of the mechanistic differences in their early-stage aggregation.

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The Alzheimer Disease Protective Mutation A2T Modulates Kinetic and Thermodynamic Properties of Amyloid-β (Aβ) Aggregation

Cited by 140 publications

References 46 publications

SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

SEPT8 modulates β-amyloidogenic processing of APP by affecting the sorting and accumulation of BACE1

Pyroglutamate-Modified Amyloid-β(3–42) Shows α-Helical Intermediates before Amyloid Formation

Alzheimer’s Protective A2T Mutation Changes the Conformational Landscape of the Aβ1–42 Monomer Differently Than Does the A2V Mutation

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