Brain-neuron targeted nanoparticles for peptide synergy therapy at dual-target of Alzheimer’s disease
Abstract
Since the complex interactions of multiple mechanisms involved in Alzheimer's disease (AD) preclude the monotherapeutic approaches from clinical application, combination therapy has become an attractive strategy for AD treatment. However, to be emphasized, the realization of the edges of combination therapy greatly depends on the reasonable choice of targets and the rational design of combination scheme. Acknowledgedly, amyloid plaques and hyperphosphorylated tau (p-tau) are two main hallmarks in AD with close pathological correlations, implying the hopeful prospect of combined intervention in them for AD treatment. Herein, we developed the nano-combination system, neuron-targeting PEG-PLA nanoparticles (CT-NP) loading two peptide drugs H102, a β-sheet breaker acting on Aβ, and NAP, a microtubule stabilizer acting on p-tau. Compared with free peptide combination, nano-combination system partly aligned the in vivo behaviors of combined peptides and enhanced peptide accumulation in lesion neurons by the guidance of targeting peptide CGN and Tet1, facilitating the therapeutic performance of peptide combination. Further, to maximize the therapeutic potential of nano-combination system, the combination ratio and mode were screened by the quantitative evaluation with combination index and U test, respectively, in vitro and in vivo. The results showed that the separated-loading CT-NP at the combination molar ratio of 2:1 (H102:NAP), CT-NP/H102 + CT-NP/NAP(2:1), generated the strongest synergistic therapeutic effects on Aβ, p-tau and their linkage, and effectually prevented neuroinflammation, reversed the neuronal damage and restored cognitive performance in 3 × Tg-AD transgenic mice. Our studies provide critical data on the effectiveness of nano-combination therapy simultaneously intervening in Aβ and p-tau, confirming the promising application of nano-combination strategy in AD treatment.
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Neuroprotective agents such as NAP, the activity-dependent neuroprotective protein generated from ADNP, have been shown to be useful in preventing the death of neurons, in order to preserve microtubules and maintain neuronal function.
“In order to preserve microtubules and maintain neuronal function, neuroprotective agents—substances such as NAP, the activity-dependent neuroprotective protein generated from ADNP—have been shown to be useful in preventing the death of neurons [211,212].”
From Recent Advances in Therapeutics for the Treatment of Alzheimer’s Disease (2024) · cites this paper as [211]
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- Authors
- Guo, Q., Li, Y., Xu, S., Wang, P., Qian, K., Yang, P., Sheng, D., Wang, L., Cheng, Y., Meng, R., Cao, J., Luo, H., Wei, Y., & Zhang, Q.
- Affiliations
- Shanghai University (CN)
- Fudan University (CN)
- Corresponding author
- Wei, Yan
- Zhang, Qizhi
- ORCID
- Venue
- Journal of Controlled Release
- Publisher
- Elsevier BV
- Published
- 2023-03
- Volume
- 355
- Pages
- 604-621
- ISSN
- 0168-3659 (ISSN-L)
- OpenAlex
- W4319262303
- Cited by
- 40
- References
- 70
- Citations by year
- 2026: 8 · 2025: 15 · 2024: 14 · 2023: 3
- FWCI
- 7.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- Locations
- Journal of Controlled Release (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Natural Science Foundation of Shanghai (19ZR140620)
- National Natural Science Foundation of China (81473150, 81690263, 82003702, 82073780)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- Alzheimer's disease, combination therapy, peptide synergy, PEG-PLA nanoparticles, amyloid-beta, hyperphosphorylated tau, NAP, CGN, TET1, dual-targeted therapy, neuroinflammation, cognitive impairment, 3xTg-AD mice, combination index
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Mice, Transgenic, Neurons, Peptides, Polyethylene Glycols, Amyloid beta-Peptides, Mice, Nanoparticles
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