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Towards Structural Restoration: Epigenetic Reprogramming and Direct Astrocyte-to-Neuron Lineage Conversion as Next-Generation Regenerative Neurotherapeutics.

Λεπτομέρειες βιβλιογραφικής εγγραφής
Τίτλος: Towards Structural Restoration: Epigenetic Reprogramming and Direct Astrocyte-to-Neuron Lineage Conversion as Next-Generation Regenerative Neurotherapeutics.
Συγγραφείς: Nguyen HM; Center for Pharmaceutical Biotechnology, College of Medicine and Pharmacy, Duy Tan University, Da Nang City, Vietnam. nguyenminhhung@dtu.edu.vn.; Faculty of Medicine, College of Medicine and Pharmacy, Duy Tan University, Da Nang City, Vietnam. nguyenminhhung@dtu.edu.vn., Nguyen LDT; Center for Pharmaceutical Biotechnology, College of Medicine and Pharmacy, Duy Tan University, Da Nang City, Vietnam.
Πηγή: Molecular neurobiology [Mol Neurobiol] 2026 Aug 10; Vol. 63 (1). Date of Electronic Publication: 2026 Aug 10.
Τύπος έκδοσης: Journal Article; Review
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE
Imprint Name(s): Original Publication: Clifton, NJ : Humana Press, c1987-
Ιατρικοί όροι (MeSH): Astrocytes*/metabolism , Astrocytes*/cytology , Neurons*/metabolism , Neurons*/cytology , Cellular Reprogramming*/genetics , Epigenesis, Genetic* , Cell Lineage* , Nerve Regeneration*, Humans ; Animals
Περίληψη: While the recent clinical approval of amyloid-targeting monoclonal antibodies represents a landmark in Alzheimer's disease (AD) management, these immunotherapies fundamentally function as agents of mitigation rather than restoration, failing to reconstitute decimated neural circuitry. Direct in situ astrocyte-to-neuron reprogramming offers a compelling regenerative alternative by leveraging the abundant endogenous glial reservoir. However, translating this cellular plasticity in vivo is severely bottlenecked by the hostile pathological microenvironment and the deeply entrenched epigenetic memory of reactive astrocytes. In this review, we delineate a tripartite neuroregenerative framework. First, we evaluate the prerequisite use of senotherapeutics to engineer a permissive parenchymal niche for nascent neuronal survival. Second, we explore epigenomic editing strategies-including CRISPR-dCas9 platforms and targeted pharmacological modulators-required to dismantle repressive heterochromatin and unlock sequestered neurogenic loci. Third, we dissect the molecular execution of reprogramming via pioneer transcription factors (TFs), emphasizing the obligatory metabolic rewiring from astrocytic glycolysis to neuronal oxidative phosphorylation (OXPHOS). Finally, to overcome formidable translational hurdles, we highlight the convergence of AI-optimized lipid nanoparticles (LNPs) for non-viral blood-brain barrier (BBB) transcytosis alongside Neurological Digital Twins (NDTs) to computationally predict the optimal presymptomatic intervention window. By harmonizing microenvironmental conditioning, epigenetic rejuvenation, and precision delivery, this systems-level blueprint provides a promising rationale for transitioning AD therapeutics from passive deceleration to active structural restoration.
(© 2026. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Competing Interests: Declarations. Literature Search and Reference Organization: A structured literature search was performed in PubMed, Web of Science, and Scopus, covering publications from 2016 to 2026. Search strategies combined controlled vocabulary (e.g., MeSH terms: Cellular Reprogramming, Epigenomics, Alzheimer's Disease, Regenerative Medicine) with relevant free-text keywords, including “astrocyte-to-neuron conversion,” “epigenetic reprogramming,” “in situ neuroregeneration,” “neurological digital twins,” and “senotherapeutics.” Additional terms such as “neuro-immune microenvironment,” “senescence-associated secretory phenotype (SASP),” and “clinical trial” were included to capture studies with broader relevance to neurotherapeutics. Eligible records were limited to peer-reviewed articles, authoritative reviews, and clinical trial reports in English. Titles and abstracts were screened for relevance, followed by a full-text review of selected articles. Reference lists of key papers were examined to identify additional pertinent studies. All references were organized using reference management software and formatted in accordance with the target journal’s style requirements. Competing interests: The authors declare no competing interests.
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Contributed Indexing: Keywords: Alzheimer’s disease; Astrocyte-to-neuron conversion; Epigenomic editing; MRNA-lipid nanoparticles; Neurological Digital Twins; Senotherapeutics
Entry Date(s): Date Created: 20260810 Date Completed: 20260810 Latest Revision: 20260810
Update Code: 20260810
DOI: 10.1007/s12035-026-06113-2
PMID: 42573852
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1559-1182
DOI:10.1007/s12035-026-06113-2