Modulation of amyloid-β aggregation by metal complexes with a dual binding mode and their delivery across the blood–brain barrier using focused ultrasound

Chan, Tiffany G.; Ruehl, Carmen L.; Morse, Sophie V.; Simon, Michelle; Rakers, Viktoria; Watts, Helena; Aprile, Francesco A.; Choi, James J.; Vilar, Ramón

doi:10.1039/d1sc02273c

Cited by 19 publications

(7 citation statements)

References 53 publications

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“…, chlorides) inhibit the aggregation of Aβ 1–40 and its N-terminal region − as well as of prion protein (PrP) fragments. , Polyoxometalate derivatives of Pt and V suppress amyloid aggregation in a mechanism involving multiple interactions: (i) the coordination of the metal, (ii) electrostatic, (iii) hydrogen, and (iv) van der Waals forces. Octahedral Co compounds, as well as square-planar Pt complexes bearing polyaromatic ligands, interact with the Aβ peptide via π–π stacking . Furthermore, hetero-multinuclear Pt–Ru complexes are able to revert amyloidosis: they regulate amyloid-induced cytotoxicity in insulinoma β-cells and significantly increase cell viability .…”

Section: Introductionmentioning

confidence: 99%

Glucosyl Platinum(II) Complexes Inhibit Aggregation of the C-Terminal Region of the Aβ Peptide

et al. 2022

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Neurodegenerative diseases are often caused by uncontrolled amyloid aggregation. Hence, many drug discovery processes are oriented to evaluate new compounds that are able to modulate self-recognition mechanisms. Herein, two related glycoconjugate pentacoordinate Pt(II) complexes were analyzed in their capacity to affect the self-aggregation processes of two amyloidogenic fragments, Aβ21–40 and Aβ25–35, of the C-terminal region of the β-amyloid (Aβ) peptide, the major component of Alzheimerʼs disease (AD) neuronal plaques. The most water-soluble complex, 1Pt dep , is able to bind both fragments and to deeply influence the morphology of peptide aggregates. Thioflavin T (ThT) binding assays, electrospray ionization mass spectrometry (ESI-MS), and ultraviolet–visible (UV–vis) absorption spectroscopy indicated that 1Pt dep shows different kinetics and mechanisms of inhibition toward the two sequences and demonstrated that the peptide aggregation inhibition is associated with a direct coordinative bond of the compound metal center to the peptides. These data support the in vitro ability of pentacoordinate Pt(II) complexes to inhibit the formation of amyloid aggregates and pave the way for the application of this class of compounds as potential neurotherapeutics.

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Section: Introductionmentioning

confidence: 99%

Glucosyl Platinum(II) Complexes Inhibit Aggregation of the C-Terminal Region of the Aβ Peptide

et al. 2022

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“…The team also performed two-photon microscopy to assess leukocyte infiltration in response to US +MB treatment and found significantly more neutrophils in the sonicated compared to the contralateral hemisphere, suggesting a role not only for brain-resident microglia but also peripheral neutrophils, the first line of defence of the innate immune system [ 37 ]. Of note, US +MB has assisted the delivery of other agents, including the GSK inhibitor AR-A014418 [ 38 ], a TrkA agonist [ 39 ], and exosomes [ 40 ] in Aβ-depositing mice, and Aβ-targeting metal complexes in wild-type mice [ 41 ]. More recently, stem cells have been delivered together with anti-Aβ antibodies [ 42 ].…”

Section: Applications Of Low-frequency Ultrasound To Alzheimer’s Mous...mentioning

confidence: 99%

Ultrasound-Mediated Bioeffects in Senescent Mice and Alzheimer’s Mouse Models

et al. 2022

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Ultrasound is routinely used for a wide range of diagnostic imaging applications. However, given that ultrasound can operate over a wide range of parameters that can all be modulated, its applicability extends far beyond the bioimaging field. In fact, the modality has emerged as a hybrid technology that effectively assists drug delivery by transiently opening the blood–brain barrier (BBB) when combined with intravenously injected microbubbles, and facilitates neuromodulation. Studies in aged mice contributed to an insight into how low-intensity ultrasound brings about its neuromodulatory effects, including increased synaptic plasticity and improved cognitive functions, with a potential role for neurogenesis and the modulation of NMDA receptor-mediated neuronal signalling. This work is complemented by studies in mouse models of Alzheimer’s disease (AD), a form of pathological aging. Here, ultrasound was mainly employed as a BBB-opening tool that clears protein aggregates via microglial activation and neuronal autophagy, thereby restoring cognition. We discuss the currently available ultrasound approaches and how studies in senescent mice are relevant for AD and can accelerate the application of low-intensity ultrasound in the clinic.

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“…10), which as expected bind to Aβ peptide His residues and inhibit aggregation. 116 Most interestingly, the authors showed that the complexes can be delivered across the BBB using focused ultrasound.…”

Section: Introductionmentioning

confidence: 99%

Targeting misfolding and aggregation of the amyloid-β peptide and mutant p53 protein using multifunctional molecules

Grcic,

Leech,

Kwan

et al. 2024

Chem. Commun.

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Modulation of amyloid-β aggregation by metal complexes with a dual binding mode and their delivery across the blood–brain barrier using focused ultrasound

Abstract: One of the key hallmarks of Alzheimer’s disease is the aggregation of the amyloid-β peptide to form fibrils. Consequently, there has been great interest in studying molecules that can disrupt...

Cited by 19 publications

References 53 publications

Glucosyl Platinum(II) Complexes Inhibit Aggregation of the C-Terminal Region of the Aβ Peptide

Glucosyl Platinum(II) Complexes Inhibit Aggregation of the C-Terminal Region of the Aβ Peptide

Ultrasound-Mediated Bioeffects in Senescent Mice and Alzheimer’s Mouse Models

Targeting misfolding and aggregation of the amyloid-β peptide and mutant p53 protein using multifunctional molecules

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