Kinetic Analysis Reveals the Identity of Aβ-Metal Complex Responsible for the Initial Aggregation of Aβ in the Synapse

Branch, Thomas; Barahona, Mauricio; Dodson, Charlotte A.; Ying, Liming

doi:10.1021/acschemneuro.7b00121

Cited by 25 publications

(21 citation statements)

References 65 publications

(149 reference statements)

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“…The metal ions released during synaptic transmission can induce amyloid-beta oligomer formation in the curved membrane of synapses. Through a combination of experimental kinetics studies and coupled reaction-diffusion simulations, we predicted that Cu (II) rather than Zn (II) plays an important role in the very early stages of Aβ aggregation in the synapse 53 . In addition, curved structures could also take place on cell debris.…”

Section: Discussionmentioning

confidence: 99%

A Novel Aβ40 Assembly at Physiological Concentration

Tahirbegi

Magness

Piersimoni

et al. 2020

Sci Rep

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Aggregates of amyloid-β (Aβ) are characteristic of Alzheimer's disease, but there is no consensus as to either the nature of the toxic molecular complex or the mechanism by which toxic aggregates are produced. We report on a novel feature of amyloid-lipid interactions where discontinuities in the lipid continuum can serve as catalytic centers for a previously unseen microscale aggregation phenomenon. We show that specific lipid membrane conditions rapidly produce long contours of lipidbound peptide, even at sub-physiological concentrations of Aβ. Using single molecule fluorescence, time-lapse TIRF microscopy and AFM imaging we characterize this phenomenon and identify some exceptional properties of the aggregation pathway which make it a likely contributor to early oligomer and fibril formation, and thus a potential critical mechanism in the etiology of AD. We infer that these amyloidogenic events occur only at areas of high membrane curvature, which suggests a range of possible mechanisms by which accumulated physiological changes may lead to their inception. The speed of the formation is in hours to days, even at 1 nM peptide concentrations. Lipid features of this type may act like an assembly line for monomeric and small oligomeric subunits of Aβ to increase their aggregation states. We conclude that under lipid environmental conditions, where catalytic centers of the observed type are common, key pathological features of AD may arise on a very short timescale under physiological concentration. A widely adopted framework to understand the biochemical underpinnings of AD is based on the amyloid cascade hypothesis, which assumes that aggregation of the Aβ peptide into oligomeric or fibrous structures triggers a cascade of toxic events that cause functional deterioration of the human brain 1. The aggregation of Aβ in cell-free solution is well studied and explained by the primary nucleation of monomers, secondary nucleation of monomers on the fibrils and the elongation of fibrils by monomer addition 2,3. For these molecular events to occur, a critical concentration of monomers of ~90 nM in solution is required 4 , far above the concentration found in vivo. Furthermore, for fibril formation in cell free systems, µM concentration of Aβ is required 5 ; while in the brain, the peptide concentration reaches only up to 4 nM 6. Given these numbers it is unlikely that the currently established in vitro mechanisms can account for the formation of plaques and tangles in the brain of AD patients 7,8. Converse to the aggregation mechanism in the absence of cells, it is well documented that interactions of Aβ with cell membranes can induce Aβ aggregation. Aβ-membrane interactions occur via prion 9 , cholesterol 10 and gangliosides 11 or non-specifically with the lipid membranes themselves 12-20. Previous studies found changes in the lipid composition of the brain in AD patients during disease progression affecting the carbon chain length, linkages, and degree of unsaturation 21. This brings to the idea that phospholipid metab...

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Section: Discussionmentioning

confidence: 99%

A Novel Aβ40 Assembly at Physiological Concentration

Tahirbegi

Magness

Piersimoni

et al. 2020

Sci Rep

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“…Research of the past two decades has led to a much improved understanding of the mechanisms of metal ion binding by Aβ peptides . There is a fundamental difference between the mechanism of metal ion binding by Aβ and that of the well‐structured metalloproteins .…”

Section: Metal Ionsmentioning

confidence: 99%

“…As discussed earlier, the basic phases of fibril formation are nucleation and fibril elongation or growth. In addition, once fibrils form, fragmentation, secondary nucleation, and fibril dissolution add greater complexity to the overall kinetics . Metal could affect any of these stages, though in different ways.…”

Section: Metal Ionsmentioning

confidence: 99%

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β‐Amyloid aggregation and heterogeneous nucleation

et al. 2019

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In this article, we consider the role of heterogeneous nucleation in β‐amyloid aggregation. Heterogeneous nucleation is more common and occurs at lower levels of supersaturation than homogeneous nucleation. The nucleation period is also the stage at which most of the polymorphism of amyloids arises, this being one of the defining features of amyloids. We focus on several well‐known heterogeneous nucleators of β‐amyloid, including lipid surfaces, especially those enriched in gangliosides and cholesterol, and divalent metal ions. These two broad classes of nucleators affect β‐amyloid particularly in light of the amphiphilicity of these peptides: the N‐terminal region, which is largely polar and charged, contains the metal binding site, whereas the C‐terminal region is aliphatic and is important in lipid binding. Notably, these two classes of nucleators can interact cooperatively, aggregation begetting greater aggregation.

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“…Such data have been obtained previously for Cu II Ab 1Àx complexes. [15][16][17] Here, we studied the reaction mechanism for Cu II binding to the model peptide Ab 4-16 and found that the reaction follows a hierarchical fashion, going through two intermediate states and then reaching the final tight complex.…”

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confidence: 99%