Cross-seeding of WT amyloid-β with Arctic but not Italian familial mutants accelerates fibril formation in Alzheimer's disease

Liang, Ruina; Tian, Yao; Viles, John H.

doi:10.1016/j.jbc.2022.102071

“…This suggests the site of nucleation on the surface of fibrils is unaffected by protonation of the histidine's. Despite the sensitivity of sequence to cross‐seeding, [17] point mutations of hydrophobic residues on the fibril surface have limited impact on secondary nucleation, which highlights the generality of the surface catalysed effect. [12] …”

mentioning

confidence: 99%

“…Other alterations in the charge on the side‐chain caused by point mutations found in familial AD, do influence fibril structure and the fibril twist periodicity. [ 17 , 18 ] However, most structures of Aβ indicate the histidine's are not in the structured core of the fibril, [19] as highlighted in supplemental Figure S10.…”

mentioning

confidence: 99%

pH Dependence of Amyloid‐β Fibril Assembly Kinetics: Unravelling the Microscopic Molecular Processes

Tian

¹

,

Viles

²

2022

Self Cite

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Central to Alzheimer's disease (AD) is the assembly of the amyloid-beta peptide (Aβ) into fibrils. A reduction in pH accompanying inflammation or subcellular compartments, may accelerate fibril formation as the pH approaches Aβ's isoelectric point (pI). Using global fitting of fibril formation kinetics over a range of pHs, we identify the impact net charge has on individual fibril assembly microscopic rate constants. We show that the primary nucleation has a strong pH dependence. The titration behaviour exhibits a midpoint or pK a of 7.0, close to the pK a of Aβ histidine imidazoles. Surprisingly, both the secondary nucleation and elongation rate constants are pH independent. This indicates the charge of Aβ, in particular histidine protonation, has little impact on this stage of Aβ assembly. These fundamental processes are key to understanding the forces that drive the assembly of Aβ into toxic oligomers and fibrils.

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“…This analysis showed that seeding activity of in vivo-derived seeds can be described quantitatively, which is confirmed by the linear correlation between the amount of added seeds and the fitting parameter M (0), evident for both mouse models and in vitro seeds (Figure E). Interestingly, the App NL‑G‑F extract, which contains Artic Aβ42 fibrils, can efficiently seed wild-type Aβ42, similarly as previously observed in vitro …”

Section: Resultsmentioning

confidence: 99%

“…Interestingly, the App NL-G-F extract, which contains Artic Aβ42 fibrils, can efficiently seed wild-type Aβ42, similarly as previously observed in vitro. 26 Morphology of In Vivo-Derived Aβ42 Fibrils. To shed light on the morphology of the in vivo-seeded fibrils, we analyzed the end products of the aggregation kinetics by TEM.…”

Section: ■ Introductionmentioning

confidence: 99%

Molecular Mechanisms of Amyloid-β Self-Assembly Seeded by In Vivo-Derived Fibrils and Inhibitory Effects of the BRICHOS Chaperone

Kumar

¹

,

Arroyo-García

²

,

Manchanda

³

et al. 2023

ACS Chem. Neurosci.

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Self-replication of amyloid-β-peptide (Aβ) fibril formation is a hallmark in Alzheimer's disease (AD). Detailed insights have been obtained in Aβ self-assembly in vitro, yet whether similar mechanisms are relevant in vivo has remained elusive. Here, we investigated the ability of in vivo-derived Aβ fibrils from two different amyloid precursor protein knock-in AD mouse models to seed Aβ42 aggregation, where we quantified the microscopic rate constants. We found that the nucleation mechanism of in vivo-derived fibril-seeded Aβ42 aggregation can be described with the same kinetic model as that in vitro. Further, we identified the inhibitory mechanism of the anti-amyloid BRICHOS chaperone on seeded Aβ42 fibrillization, revealing a suppression of secondary nucleation and fibril elongation, which is strikingly similar as observed in vitro. These findings hence provide a molecular understanding of the Aβ42 nucleation process triggered by in vivo-derived Aβ42 propagons, providing a framework for the search for new AD therapeutics.

show abstract

“…This suggests the site of nucleation on the surface of fibrils is unaffected by protonation of the histidine's. Despite the sensitivity of sequence to cross-seeding, [17] point mutations of hydrophobic residues on the fibril surface have limited impact on secondary nucleation, which highlights the generality of the surface catalysed effect. [12] The change in protonation state of the histidine sidechains does not appear to affect the fibril morphology, Figure 4.…”

mentioning

confidence: 99%

pH Dependence of Amyloid‐β Fibril Assembly Kinetics: Unravelling the Microscopic Molecular Processes

Tian

¹

,

Viles

²

2022

Angewandte Chemie

Self Cite

2

0

View full text Add to dashboard Cite

Central to Alzheimer's disease (AD) is the assembly of the amyloid-beta peptide (Aβ) into fibrils. A reduction in pH accompanying inflammation or subcellular compartments, may accelerate fibril formation as the pH approaches Aβ's isoelectric point (pI). Using global fitting of fibril formation kinetics over a range of pHs, we identify the impact net charge has on individual fibril assembly microscopic rate constants. We show that the primary nucleation has a strong pH dependence. The titration behaviour exhibits a midpoint or pK a of 7.0, close to the pK a of Aβ histidine imidazoles. Surprisingly, both the secondary nucleation and elongation rate constants are pH independent. This indicates the charge of Aβ, in particular histidine protonation, has little impact on this stage of Aβ assembly. These fundamental processes are key to understanding the forces that drive the assembly of Aβ into toxic oligomers and fibrils.

show abstract

Cross-seeding of WT amyloid-β with Arctic but not Italian familial mutants accelerates fibril formation in Alzheimer's disease

Cited by 10 publications

References 44 publications

pH Dependence of Amyloid‐β Fibril Assembly Kinetics: Unravelling the Microscopic Molecular Processes

pH Dependence of Amyloid‐β Fibril Assembly Kinetics: Unravelling the Microscopic Molecular Processes

Molecular Mechanisms of Amyloid-β Self-Assembly Seeded by In Vivo-Derived Fibrils and Inhibitory Effects of the BRICHOS Chaperone

pH Dependence of Amyloid‐β Fibril Assembly Kinetics: Unravelling the Microscopic Molecular Processes

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