Brain Targeting and Aβ Binding Bifunctional Nanoparticles Inhibit Amyloid Protein Aggregation in APP/PS1 Transgenic Mice

Zhang, Xiancheng; Zhang, Xiaoyu; Li, You; Zhong, Manli; Zhao, Pan; Guo, Chuangxin; Xu, He; Wang, Tao; Gao, Huiling

doi:10.1021/acschemneuro.1c00035

Cited by 21 publications

(22 citation statements)

References 70 publications

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“…Despite using BBB cell models or cell membrane receptors is a direct and convenient method for biopanning, it is well known that the in vitro condition can be quite different from the complex brain environment in vivo . Phage display in vivo has been proven to be very effective in selecting phages with high organ specificity after systemic injection 38 , and several BBB penetrating peptides from in vivo selection have been identified and applied to targeted delivery of AD drugs 61 , 103 .…”

Section: Brain Drug Delivery In Ad: Phage Display Derived-peptides Pe...mentioning

confidence: 99%

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Zhang¹,

Zhang²,

Gao³

et al. 2022

Theranostics

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Alzheimer's disease (AD) is an incurable and fatal progressive neurodegenerative disorder associated with memory and cognition impairment. AD is one of the top medical care concerns across the world with a projected economic burden of $2 trillion by 2030. To date, however, there remains no effective disease-modifying therapy available. It is more important than ever to reveal novel therapeutic approaches. Peptide-based biotherapeutics has been a great potential strategy attributed to their distinct and superior biochemical characteristics, such as reproducible chemical synthesis and modification, rapid cell and tissue permeability, and fast blood clearance. Phage display, one of today's most powerful platforms, allows selection and identification of suitable peptide drug candidates with high affinities and specificity toward target, demonstrating the potential to overcome challenges and limitations in AD diagnosis/treatment. We aim to provide the first comprehensive review to summarize the status in this research direction. The biological overview of phage display is described, including basic biology of the phage vectors and construction principle of phage library, biopanning procedure, mirror image phage display, and various binding affinity evaluation approaches. Further, the applications of phage display in AD therapy, targeted drug delivery, and early detection are presented. Finally, we discuss the current challenges and offer a future outlook for further advancing the potential application of phage display on AD and other neurodegenerative diseases.

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Section: Brain Drug Delivery In Ad: Phage Display Derived-peptides Pe...mentioning

confidence: 99%

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Zhang¹,

Zhang²,

Gao³

et al. 2022

Theranostics

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“…Patients with COVID-19 are predicted to have a higher risk to develop neurodegenerative diseases (Chana-Cuevas et al 2020 ; Dolatshahi et al 2021 ; Tavassoly et al 2020 ). The analysis of potential effects of SARS-CoV-2 proteins indicates that the infection interferes with autophagosome–lysosome fusion (Miao et al 2021 ; Zhang et al 2021b ). Particularly, the open reading frame 3a (ORF3a) of SARS-CoV-2 blocks the fusion between autophagosomes and lysosomes and thus the autophagic flux.…”

Section: Autophagy In Diseasementioning

confidence: 99%

“…Particularly, the open reading frame 3a (ORF3a) of SARS-CoV-2 blocks the fusion between autophagosomes and lysosomes and thus the autophagic flux. ORF3a was found to interact with VPS39, a process that prevents the assembly of fusion machinery, leading to the accumulation of autophagosomes (Miao et al 2021 ; Zhang et al 2021b ). Notably, disruption of ORF3a-VPS39 interaction by a point mutation diminishes the blocking effect of ORF3a.…”

Section: Autophagy In Diseasementioning

confidence: 99%

Protein clearance strategies for disease intervention

Hommen

Bilican

2021

J Neural Transm

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Protein homeostasis, or proteostasis, is essential for cell function and viability. Unwanted, damaged, misfolded and aggregated proteins are degraded by the ubiquitin–proteasome system (UPS) and the autophagy-lysosome pathway. Growing evidence indicates that alterations in these major proteolytic mechanisms lead to a demise in proteostasis, contributing to the onset and development of distinct diseases. Indeed, dysregulation of the UPS or autophagy is linked to several neurodegenerative, infectious and inflammatory disorders as well as cancer. Thus, modulation of protein clearance pathways is a promising approach for therapeutics. In this review, we discuss recent findings and open questions on how targeting proteolytic mechanisms could be applied for disease intervention.

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“…Currently, intranasal administration is the recommended method for intracerebral administration to avoid the necessity to penetrate the blood-brain barrier [65][66][67]. Therefore, in this study, FITC-labeled PCu was administered to mice through the nasal cavity.…”

Section: Pcu Enters the Brain After Intranasal Administrationmentioning

confidence: 99%

“…First, dissolved the Aβ1-42 lyophilized powder in HFIP solution to a final concentration of 1.0 mg/mL, then incubated for 2 h at 4 • C, sonicated it in an ice bath for 2 min, and centrifuged the resulting solution (4 • C, 12,000 rpm, 30 min) to remove pre-existing aggregates [67]. Collected 75% of the top supernatant to freeze-dry storing at −20 • C for use.…”

Section: Thioflavin T Assaysmentioning

confidence: 99%

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

Zhang

Zhong

et al. 2021

IJMS

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Copper (Cu) has been implicated in the progression of Alzheimer’s disease (AD), and aggregation of Cu and amyloid β peptide (Aβ) are considered key pathological features of AD. Metal chelators are considered to be potential therapeutic agents for AD because of their capacity to reduce metal ion-induced Aβ aggregation through the regulation of metal ion distribution. Here, we used phage display technology to screen, synthesize, and evaluate a novel Cu(II)-binding peptide that specifically blocked Cu-triggered Aβ aggregation. The Cu(II)-binding peptide (S-A-Q-I-A-P-H, PCu) identified from the phage display heptapeptide library was used to explore the mechanism of PCu inhibition of Cu2+-mediated Aβ aggregation and Aβ production. In vitro experiments revealed that PCu directly inhibited Cu2+-mediated Aβ aggregation and regulated copper levels to reduce biological toxicity. Furthermore, PCu reduced the production of Aβ by inhibiting Cu2+-induced BACE1 expression and improving Cu(II)-mediated cell oxidative damage. Cell culture experiments further demonstrated that PCu had relatively low toxicity. This Cu(II)-binding peptide that we have identified using phage display technology provides a potential therapeutic approach to prevent or treat AD.

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Brain Targeting and Aβ Binding Bifunctional Nanoparticles Inhibit Amyloid Protein Aggregation in APP/PS1 Transgenic Mice

Cited by 21 publications

References 70 publications

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Phage display derived peptides for Alzheimer's disease therapy and diagnosis

Protein clearance strategies for disease intervention

A Novel Cu(II)-Binding Peptide Identified by Phage Display Inhibits Cu2+-Mediated Aβ Aggregation

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