A robust preparation method for the amyloidogenic and intrinsically disordered amyloid‐α peptide

Kuhn, Ariel J.; Raskatov, Jevgenij A.

doi:10.1002/psc.3414

Cited by 2 publications

(2 citation statements)

References 24 publications

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“…42,43 Herein, we report a biophysical and biological analysis of the relationship between Aα and Aβ in an effort to deconvolute the role of Aα in AD. Aα 17−40 was selected over Aα 17−42 as Aα 17−42 is too hydrophobic compared to Aβ, 44 making it difficult to use the same preparation protocols. In addition, even upon dissolution, Aα 17−42 precipitates out of the solution (data not shown), making it challenging to study its aggregation kinetics.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Amyloid-α Peptide Formed through Alternative Processing of the Amyloid Precursor Protein Attenuates Alzheimer’s Amyloid-β Toxicity via Cross-Chaperoning

Kuhn,

Chan,

Sajimon

et al. 2024

J. Am. Chem. Soc.

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Amyloid aggregation is a key feature of Alzheimer's disease (AD) and a primary target for past and present therapeutic efforts. Recent research is making it increasingly clear that the heterogeneity of amyloid deposits, extending past the commonly targeted amyloid-β (Aβ), must be considered for successful therapy. We recently demonstrated that amyloid-α (Aα or p3), a C-terminal peptidic fragment of Aβ, aggregates rapidly to form amyloids and can expedite the aggregation of Aβ through seeding. Here, we advance the understanding of Aα biophysics and biology in several important ways. We report the first cryogenic electron microscopy (cryo-EM) structure of an Aα amyloid fibril, proving unambiguously that the peptide is fibrillogenic. We demonstrate that Aα induces Aβ to form amyloid aggregates that are less toxic than pure Aβ aggregates and use nuclear magnetic resonance spectroscopy (NMR) to provide insights into specific interactions between Aα and Aβ in solution. This is the first evidence that Aα can coassemble with Aβ and alter its biological effects at relatively low concentrations. Based on the above, we urge researchers in the field to re-examine the significance of Aα in AD.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Amyloid-α Peptide Formed through Alternative Processing of the Amyloid Precursor Protein Attenuates Alzheimer’s Amyloid-β Toxicity via Cross-Chaperoning

Kuhn,

Chan,

Sajimon

et al. 2024

J. Am. Chem. Soc.

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“…However, they are difficult to detect because many commonly used Aβ antibodies are not selective for Aβ 1-42 and cross-react with p3 fragments and other N-terminally abridged variants [ 117 ]. In addition, many established protocols for isolating Aβ peptides from brain and CSF samples are not suitable for p3 peptides due to their high hydrophobicity and insolubility, which excluded them from many studies that evaluated Aβ levels [ 118 ]. Moreover, since several non-canonical proteases such as IDE, NEP and MMP9 have cleavage motifs within the p3 sequence ( Figure 2 B), it is likely that additional p3 peptides with highly variable C-termini exist.…”

Section: Processes That Lead To the Generation Of Non-canonical Aβ Va...mentioning

confidence: 99%

The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease

Busch

Eggert²,

Bufe

2022

Cells

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Recent advances have placed the pro-inflammatory activity of amyloid β (Aβ) on microglia cells as the focus of research on Alzheimer’s Disease (AD). Researchers are confronted with an astonishing spectrum of over 100 different Aβ variants with variable length and chemical modifications. With the exception of Aβ1-42 and Aβ1-40, the biological significance of most peptides for AD is as yet insufficiently understood. We therefore aim to provide a comprehensive overview of the contributions of these neglected Aβ variants to microglia activation. First, the impact of Aβ receptors, signaling cascades, scavenger mechanisms, and genetic variations on the physiological responses towards various Aβ species is described. Furthermore, we discuss the importance of different types of amyloid precursor protein processing for the generation of these Aβ variants in microglia, astrocytes, oligodendrocytes, and neurons, and highlight how alterations in secondary structures and oligomerization affect Aβ neurotoxicity. In sum, the data indicate that gene polymorphisms in Aβ-driven signaling pathways in combination with the production and activity of different Aβ variants might be crucial factors for the initiation and progression of different forms of AD. A deeper assessment of their interplay with glial cells may pave the way towards novel therapeutic strategies for individualized medicine.

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A robust preparation method for the amyloidogenic and intrinsically disordered amyloid‐α peptide

Cited by 2 publications

References 24 publications

Amyloid-α Peptide Formed through Alternative Processing of the Amyloid Precursor Protein Attenuates Alzheimer’s Amyloid-β Toxicity via Cross-Chaperoning

Amyloid-α Peptide Formed through Alternative Processing of the Amyloid Precursor Protein Attenuates Alzheimer’s Amyloid-β Toxicity via Cross-Chaperoning

The Hidden Role of Non-Canonical Amyloid β Isoforms in Alzheimer’s Disease

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