ArticleJournal of neuroinflammation2026
Epigenetic brain reprogramming rejuvenates neuro-immune circuits to reverse Alzheimer's disease pathology and systemic bone loss.
Article in Journal of neuroinflammation, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Alzheimer's disease (AD) is characterized by progressive neurodegeneration, neuroinflammation, and systemic comorbidities, yet disease-modifying therapies remain elusive. Here, we show that partial epigenetic reprogramming via brain-restricted expression of Oct4, Sox2, and Klf4 (OSK) restores neuronal and neuroimmune homeostasis without loss of cellular identity. In APP/PS1 mice, OSK reprogramming improves cognitive performance across disease stages, reduces amyloid-β deposition, attenuates microglial activation, preserves synaptic integrity, and limits neuronal apoptosis. Mechanistically, reduced representation bisulfite sequencing reveals widespread reversal of AD-associated DNA methylation patterns, which is dependent on Tet2-mediated demethylation, establishing epigenetic rejuvenation as a key driver of functional recovery. Unexpectedly, brain-restricted OSK reprogramming also ameliorates systemic bone loss by reshaping brain-derived extracellular vesicle signaling, including modulation of miR-483-5p, thereby restoring osteogenic capacity. Together, these findings identify partial epigenetic reprogramming as a strategy to rewire neuro-immune circuits and link central nervous system rejuvenation to peripheral tissue homeostasis, providing a conceptual framework for targeting both neurodegeneration and its systemic consequences in AD.
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