Towards Structural Restoration: Epigenetic Reprogramming and Direct Astrocyte-to-Neuron Lineage Conversion as
Hung M Nguyen1,2, Long D T Nguyen3
1Center for Pharmaceutical Biotechnology, College of Medicine and Pharmacy, Duy Tan University, Da Nang City, Vietnam. nguyenminhhung@dtu.edu.vn.
Molecular Neurobiology
|August 10, 2026
Summary
This review proposes a novel framework for Alzheimer's disease (AD) treatment, shifting from mitigation to neural restoration via astrocyte-to-neuron reprogramming. It outlines strategies for microenvironment conditioning, epigenetic editing, and precision delivery for AD neuroregeneration.
Area of Science:
- Neuroscience
- Regenerative Medicine
- Biotechnology
Background:
- Current Alzheimer's disease (AD) therapies, like monoclonal antibodies, primarily mitigate pathology but do not restore lost neural circuitry.
- Direct in situ reprogramming of astrocytes into neurons presents a regenerative approach, but faces challenges from the pathological brain environment and astrocyte epigenetic memory.
Purpose of the Study:
- To present a tripartite neuroregenerative framework for Alzheimer's disease (AD) that aims to restore neural circuitry.
- To address the limitations of current AD treatments by proposing a regenerative strategy.
Main Methods:
- Evaluating senotherapeutics to create a permissive niche for new neurons.
- Exploring epigenomic editing (CRISPR-dCas9, pharmacological modulators) to overcome astrocyte epigenetic barriers.
- Investigating pioneer transcription factors and metabolic rewiring (glycolysis to oxidative phosphorylation) for reprogramming.
- Highlighting AI-optimized lipid nanoparticles (LNPs) for blood-brain barrier (BBB) transcytosis and Neurological Digital Twins (NDTs) for intervention timing.
Main Results:
- The proposed framework integrates microenvironmental conditioning, epigenetic rejuvenation, and precision delivery systems.
- AI-optimized LNPs and NDTs offer potential solutions for overcoming translational hurdles in AD neuroregeneration.
- The framework facilitates the transition from passive disease deceleration to active structural restoration in AD.
Conclusions:
- A systems-level blueprint combining environmental, epigenetic, and delivery strategies offers a promising path for AD neuroregeneration.
- This approach moves beyond mitigation towards active restoration of neural circuits in Alzheimer's disease.
- The convergence of advanced biotechnologies and computational tools is key to realizing in vivo cellular reprogramming for AD.
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