A self-destructive nanosweeper that captures and clears amyloid β-peptides

Abnormal accumulation of β-amyloid (Aβ) peptide aggregates in the brain is a major hallmark of Alzheimer's disease (AD). Aβ aggregates interfere with neuronal communications, ultimately causing neuronal damage and brain atrophy. Much effort has been made to develop AD treatments that suppress Aβ aggregate formation, thereby attenuating Aβ-induced neurotoxicity. Here, the design of Aβ nanodepletors consisting of ultralarge mesoporous silica nanostructures and anti-Aβ single-chain variable fragments, with the goal of targeting and eliminating aggregative Aβ monomers, is reported. The Aβ nanodepletors impart a notable decline in Aβ aggregate formation, resulting in significant mitigation of Aβ-induced neurotoxicity in vitro. Furthermore, stereotaxic injections of Aβ nanodepletors into the brain of an AD mouse model system successfully suppress Aβ plaque formation in vivo up to ≈30%, suggesting that Aβ nanodepletors can serve as a promising antiamylodoisis material.aged 65 and older are living with AD, [4] which accounts for an estimated 60-80% of dementia.Accumulation of extracellular β-amyloid (Aβ) plaques and intracellular tau proteinderived neurofibrillary tangles are major hallmarks of Alzheimer-associated brain damages in AD patients. These features are being explored from the perspective of pathological diagnosis and clinical treatment of AD. [5,6] Aβ monomers, which are derived from the cleavage of amyloid precursor protein by βand γ-secretase, [7] assemble into toxic Aβ oligomers and aggregates having cross β-sheet-rich secondary structures that induce neuronal damages. [8][9][10][11] Ultimately, the self-assembly process leads to the deposition of amyloid plaques, a strong and stable network that is difficult to break. Hence, removing monomeric Aβ at the early stage of dementia is thought to be a promising strategy for slowing the progression of AD. [12][13][14][15][16] Here, we report an Aβ-depleting nanostructure (denoted hereafter as Aβ nanodepletors) that can selectively capture and clear Aβ peptide monomers in brain (Scheme 1).

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“…Hence, removing monomeric Aβ at the early stage of dementia is thought to be a promising strategy for slowing the progression of AD. [ 12–16 ]…”

Section: Introductionmentioning

confidence: 99%

Silica Nanodepletors: Targeting and Clearing Alzheimer's β‐Amyloid Plaques

Jung

Chung

Wilton

et al. 2020

Adv Funct Materials

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“…Thus, blocking the combined action of β‐ and γ‐secretases as well as decreasing the level of Aβ assembly have been used to treat and/or prevent AD . Emerging evidence indicates that the level of Aβ accumulation is not only dependent on its generation but also dependent on its degradation . Inspired by this vision, natural Aβ‐degrading enzymes have been developed as promising therapeutics against AD.…”

Section: Methodsmentioning

confidence: 99%

A Near‐Infrared‐Controllable Artificial Metalloprotease Used for Degrading Amyloid‐β Monomers and Aggregates

Wang

Gao

et al. 2019

Chemistry A European J

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Proteolysis of amyloid‐β (Aβ) is a promising approach against Alzheimer's disease. However, it is not feasible to employ natural hydrolases directly because of their cumbersome preparation and purification, poor stability, and hazardous immunogenicity. Therefore, artificial enzymes have been developed as potential alternatives to natural hydrolases. Since specific cleavage sites of Aβ are usually embedded inside the β‐sheet structures that restrict access by artificial enzymes, this strongly hinders their efficiency for practical applications. Herein, we construct a NIR (near‐IR) controllable artificial metalloprotease (MoS2‐Co) using a molybdenum disulfide nanosheet (MoS2) and a cobalt complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (Codota). Evidenced by detailed experimental and theoretical studies, the NIR‐enhanced MoS2‐Co can circumvent the restriction by simultaneously inhibition of β‐sheet formation and destroying β‐sheet structures of the preformed Aβ aggregates in living cell. Furthermore, our designed MoS2‐Co is an easy to graft Aβ‐target agent that prevents misdirected or undesirable hydrolysis reactions, and has been demonstrated to cross the blood brain barrier. This method can be adapted for hydrolysis of other kinds of amyloids.

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“…Luo et al 97 have developed "nanosweepers" (M 3 ) that not only capture extracellular Aβ and direct it into cells but also upregulate autophagy and digestion of Aβ. The nanosweepers are composed of a cationic chitosan core with PEGylated GKLVFF (that can co-assemble with Aβ) and Becln-1 (that induces autophagy to degrade Aβ).…”

Section: Aβ Targeting Nanosweepersmentioning

confidence: 99%

“…M 3 is a multifunctional peptide-polymer that could provide a novel therapeutic approach for the treatment of AD, by clearance of Aβ. 97 By design, it is not a good aggregation inhibitor and could be useful in combination with additional therapies.…”

Section: Aβ Targeting Nanosweepersmentioning

confidence: 99%

Liposome delivery systems for the treatment of Alzheimer’s disease

Ross

Taylor

Fullwood

et al. 2018

IJN

158

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Alzheimer’s disease (AD) will affect around 115 million people worldwide by the year 2050. It is associated with the accumulation of misfolded and aggregated proteins (β-amyloid and tau) in the senile plaques and neurofibrillary tangles found in the brain. Currently available drugs for AD only temporarily alleviate symptoms and do not slow the inevitable progression of this disease. New drugs are required that act on key pathologies in order to arrest or reverse cognitive decline. However, there has been a spectacular failure rate in clinical trials of conventional small molecule drugs or biological agents. Targeted nanoliposomes represent a viable and promising drug delivery system for AD that have not yet reached clinical trials. They are biocompatible, highly flexible, and have the potential to carry many different types of therapeutic molecules across the blood–brain barrier (BBB) and into brain cells. They can be tailored to extend blood circulation time and can be directed against individual or multiple pathological targets. Modifications so far have included the use of brain-penetrating peptides, together with Aβ-targeting ligands, such as phosphatidic acid, curcumin, and a retro-inverted peptide that inhibits Aβ aggregation. Combining several modifications together into multifunctional liposomes is currently a research area of great interest. This review focuses on recent liposomal approaches to AD therapy, including mechanisms involved in facilitating their passage across the BBB, and the evaluation of new therapeutic agents for blocking Aβ and/or tau aggregation.

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A self-destructive nanosweeper that captures and clears amyloid β-peptides

Cited by 158 publications

References 46 publications

Silica Nanodepletors: Targeting and Clearing Alzheimer's β‐Amyloid Plaques

Silica Nanodepletors: Targeting and Clearing Alzheimer's β‐Amyloid Plaques

A Near‐Infrared‐Controllable Artificial Metalloprotease Used for Degrading Amyloid‐β Monomers and Aggregates

Liposome delivery systems for the treatment of Alzheimer’s disease

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A self-destructive nanosweeper that captures and clears amyloid β-peptides

Cited by 158 publications

References 46 publications

Silica Nanodepletors: Targeting and Clearing Alzheimer's β‐Amyloid Plaques

Silica Nanodepletors: Targeting and Clearing Alzheimer's β‐Amyloid Plaques

A Near‐Infrared‐Controllable Artificial Metalloprotease Used for Degrading Amyloid‐β Monomers and Aggregates

Liposome delivery systems for the treatment of Alzheimer&rsquo;s disease

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Product

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About

Liposome delivery systems for the treatment of Alzheimer’s disease