Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer’s Disease?

Natale, Giuseppe Di; Sabatino, Giuseppina; Sciacca, Michele F.M.; Tosto, Rita; Milardi, Danilo; Pappalardo, Giuseppe

doi:10.3390/molecules27165066

Cited by 16 publications

(11 citation statements)

References 178 publications

(244 reference statements)

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“…The major component of senile plaques is an aggregation of the amyloid β-protein (Aβ), a peptide of 39–43 amino acids, which is cleaved from an amyloid precursor protein . Many factors such as lipid membranes and metal ions induce the aggregation of Aβ into a variety of structures such as oligomers and fibrils. ,− Since aggregates are cytotoxic, it is widely accepted that the aggregation of Aβ is deeply involved in the onset and progression of AD. − Complementary peptides and cyclic peptides that bind to the target Aβ region were designed to inhibit Aβ aggregation based on the amino acid sequence of Aβ with the β structure. ,− …”

Section: Introductionmentioning

confidence: 99%

Cyclization of Peptides Enhances the Inhibitory Activity against Ganglioside-Induced Aβ Fibril Formation

Miyamoto,

Sato,

Matsubara

2023

ACS Chem. Neurosci.

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Alzheimer’s disease is a progressive neurodegenerative disease and is the most common cause of dementia. It has been reported that the assembly of amyloid β-protein (Aβ) on the cell membrane is induced by the interaction of the Aβ monomer with gangliosides such as GM1. The ganglioside-bound Aβ (GAβ) complex acts as a seed to promote the toxic assembly of the Aβ fibrils. In a previous study, we found that a GM1 cluster-binding peptide (GCBP) specifically recognizes Aβ-sensitive ganglioside nanoclusters and inhibits the assembly of Aβ on a GM1-containing lipid membrane. In this study, cysteine-substituted double mutants of GCBP were designed and cyclized by intramolecular disulfide bond formation. Affinity assays indicated that one of the cyclic peptides had a higher affinity to a GM1-containing membrane compared to that of GCBP. Furthermore, surface topography analysis indicated that this peptide recognizes GM1 nanoclusters on the lipid membrane. An evaluation of the inhibitory kinetics indicated that the cyclic peptide could inhibit the formation of Aβ fibrils with an IC50 value of 1.2 fM, which is 10,000-fold higher than that of GCBP. The cyclic peptide was also shown to have a clearance effect on Aβ fibrils deposited on the lipid membrane and suppressed the formation of toxic Aβ assemblies. Our results indicate that the cyclic peptide that binds to the Aβ-sensitive ganglioside nanocluster is a potential novel inhibitor of ganglioside-induced Aβ assembly.

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Section: Introductionmentioning

confidence: 99%

Cyclization of Peptides Enhances the Inhibitory Activity against Ganglioside-Induced Aβ Fibril Formation

Miyamoto,

Sato,

Matsubara

2023

ACS Chem. Neurosci.

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“…Amyloid-β can also insert into the cell membrane forming pore-like structures with the potential to disrupt normal cellular functions. 68,69 However, it was not our intention here to investigate lipids and associated lipoproteins as a contributing factor in the evolution of AD, and this subject has been discussed in detail elsewhere. 70 Plaques identified within AD tissues from different affected areas and neurologically healthy tissues using this label-free approach frequently exhibited extensive carbonate and calcium deposits, which are consistent in their properties with isolated amyloid plaque cores that we have described previously.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues

Everett,

Brooks,

Tjendana Tjhin

et al. 2024

ACS Chem. Neurosci.

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The accumulation of amyloid plaques and increased brain redox burdens are neuropathological hallmarks of Alzheimer's disease. Altered metabolism of essential biometals is another feature of Alzheimer's, with amyloid plaques representing sites of disturbed metal homeostasis. Despite these observations, metal-targeting disease treatments have not been therapeutically effective to date. A better understanding of amyloid plaque composition and the role of the metals associated with them is critical. To establish this knowledge, the ability to resolve chemical variations at nanometer length scales relevant to biology is essential. Here, we present a methodology for the label-free, nanoscale chemical characterization of amyloid plaques within human Alzheimer's disease tissue using synchrotron X-ray spectromicroscopy. Our approach exploits a C−H carbon absorption feature, consistent with the presence of lipids, to visualize amyloid plaques selectively against the tissue background, allowing chemical analysis to be performed without the addition of amyloid dyes that alter the native sample chemistry. Using this approach, we show that amyloid plaques contain elevated levels of calcium, carbonates, and iron compared to the surrounding brain tissue. Chemical analysis of iron within plaques revealed the presence of chemically reduced, low-oxidation-state phases, including ferromagnetic metallic iron. The zero-oxidation state of ferromagnetic iron determines its high chemical reactivity and so may contribute to the redox burden in the Alzheimer's brain and thus drive neurodegeneration. Ferromagnetic metallic iron has no established physiological function in the brain and may represent a target for therapies designed to lower redox burdens in Alzheimer's disease. Additionally, ferromagnetic metallic iron has magnetic properties that are distinct from the iron oxide forms predominant in tissue, which might be exploitable for the in vivo detection of amyloid pathologies using magnetically sensitive imaging. We anticipate that this label-free X-ray imaging approach will provide further insights into the chemical composition of amyloid plaques, facilitating better understanding of how plaques influence the course of Alzheimer's disease.

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“…However, throughout the years the research field has been evolving to the design of pharmacological agents able to tackle multiple targets of the disease. In this sense, many complementary hypotheses to protein misfolding have arisen around it as alternatives to give a better understanding of AD and as valuable options to elucidate new biological targets. , Herein, we discuss two of them: metallic ion dysregulation and oxidative stress, from a beta amyloid peptide (Aβ) point of view. This review will focus on two essential metal cations (copper and iron) and one exogenous metal (aluminum) and their role in the increase of oxidative stress related to AD from experimental and computational means and in the multifunctional ligands that have been proposed in order to stop some causes of the disease.…”

Section: Introductionmentioning

confidence: 99%

Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer’s Disease: Experimental and Computational Insights

et al. 2023

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Alzheimer’s disease (AD) is the most common form of dementia, affecting millions of people around the world. Even though the causes of AD are not completely understood due to its multifactorial nature, some neuropathological hallmarks of its development have been related to the high concentration of some metal cations. These roles include the participation of these metal cations in the production of reactive oxygen species, which have been involved in neuronal damage. In order to avoid the increment in the oxidative stress, multifunctional ligands used to coordinate these metal cations have been proposed as a possible treatment to AD. In this review, we present the recent advances in experimental and computational works aiming to understand the role of two redox active and essential transition-metal cations (Cu and Fe) and one nonbiological metal (Al) and the recent proposals on the development of multifunctional ligands to stop or revert the damaging effects promoted by these metal cations.

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Aβ and Tau Interact with Metal Ions, Lipid Membranes and Peptide-Based Amyloid Inhibitors: Are These Common Features Relevant in Alzheimer’s Disease?

Cited by 16 publications

References 178 publications

Cyclization of Peptides Enhances the Inhibitory Activity against Ganglioside-Induced Aβ Fibril Formation

Cyclization of Peptides Enhances the Inhibitory Activity against Ganglioside-Induced Aβ Fibril Formation

Label-Free In Situ Chemical Characterization of Amyloid Plaques in Human Brain Tissues

Role of Metal Cations of Copper, Iron, and Aluminum and Multifunctional Ligands in Alzheimer’s Disease: Experimental and Computational Insights

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