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MicroRNA-195 liposomes for therapy of Alzheimer's disease
Dan Su1, Zhong Chen2, Xiaobin An1
1Department of Pharmacology (The State-Province Key Laboratories of Biomedicine-Pharmaceutics of China), College of Pharmacy of Harbin Medical University, Harbin, Heilongjiang Province, China.
Abstract:
The complex etiologies and mechanisms of Alzheimer's disease (AD) underscore the importance for devising multitarget drugs to achieve effective therapy. MicroRNAs (miRNAs) are capable of concurrently regulating the expression of multiple proteins by selectively targeting disease- associated genes in a sequence-specific fashion. Nonetheless, as RNA-based drugs, their stability in the circulation and capacity of traversing the blood-brain barrier (BBB) is largely compromised, thereby limiting their potential clinical applications. In this study, we formulated the nanoliposomes encapsulating polyethyleneimine (PEI)/miR-195 complex (DPMT@PEI/miR-195) that was engineered through dual modifications to contain P-aminophenyl-alpha-d-mannopyranoside (MAN) and cationic cell-penetrating peptide (TAT). DPMT@PEI/miR-195 exhibited the enhanced BBB- and cell membrane penetrating capability. As expected, we observed that DPMT@PEI/miR-195 administered through intravenous tail injection of produced greater effectiveness than donepezil and the same range of effect as aducanumab in alleviating the cognitive decline in 7-month-old APP/PS1 mice. Moreover, the combination treatment with DPMT@PEI/miR-195 and donepezil effectively ameliorated the deterioration of cognition in 16-month-old APP/PS1 mice, with enhanced effects than either DPMT@PEI/miR-195 or donepezil alone. Furthermore, DPMT@PEI/miR-195 effectively attenuated the positive signals of Aβ, AT8, and CD68 in APP/PS1 mice without notable side effects. Our findings indicate DPMT@PEI/miR-195 as a promising potentially new agent or approach for the prophylaxis and treatment of early and advanced stages of Alzheimer's disease.
Insights
A novel nanoliposome drug delivery system, DPMT@PEI/miR-195, shows promise for Alzheimer's disease (AD) treatment. It effectively alleviates cognitive decline and reduces AD pathology markers in mouse models, offering a potential new therapeutic approach.
Area of Science:
- Biomedical Engineering
- Neuroscience
- Pharmacology
Background:
- Alzheimer's disease (AD) pathogenesis is complex, necessitating multitarget therapies.
- MicroRNAs (miRNAs) offer potential as RNA-based drugs but face challenges with stability and blood-brain barrier (BBB) penetration.
- Current treatments have limitations, driving the need for innovative drug delivery systems.
Purpose of the Study:
- To develop and evaluate a novel nanoliposome-based drug delivery system for enhanced miRNA therapy in Alzheimer's disease.
- To assess the efficacy of the engineered nanoliposomes (DPMT@PEI/miR-195) in improving BBB and cell membrane penetration.
- To investigate the therapeutic potential of DPMT@PEI/miR-195 in ameliorating cognitive decline and neuropathological hallmarks in AD mouse models.
Main Methods:
- Formulation of dual-modified nanoliposomes encapsulating polyethyleneimine (PEI)/miR-195 complex, incorporating P-aminophenyl-alpha-d-mannopyranoside (MAN) and TAT peptide.
- Evaluation of BBB and cell membrane penetrating capabilities of the engineered nanoliposomes.
- Intravenous administration of DPMT@PEI/miR-195 in APP/PS1 mouse models of Alzheimer's disease, assessing cognitive function and neuropathology.
Main Results:
- DPMT@PEI/miR-195 demonstrated enhanced BBB and cell membrane penetration.
- The nanoliposome formulation effectively alleviated cognitive decline in APP/PS1 mice, comparable to aducanumab and superior to donepezil in younger mice.
- Combination therapy with DPMT@PEI/miR-195 and donepezil showed enhanced efficacy in older APP/PS1 mice, reducing Aβ, AT8, and CD68 signals without significant side effects.
Conclusions:
- DPMT@PEI/miR-195 represents a promising nanoliposome-based therapeutic strategy for Alzheimer's disease.
- The dual modification strategy enhances drug delivery across the BBB, improving therapeutic outcomes.
- This approach holds potential for both prophylaxis and treatment of early and advanced stages of Alzheimer's disease.
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