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Local brain reprogramming mitigates Alzheimer's disease and associated bone loss

ABSTRACT: Alzheimer's disease (AD) is a debilitating neurodegenerative disorder marked by glia cell inflammation, neuron loss, cognitive impairment, and systemic dysfunctions, including bone loss. The progression of AD is accompanied by aging and epigenetic alterations that disrupt cellular homeostasis. Here, we demonstrate that a coexpression vector (AAV-OSK) containing Oct4, Sox2, and Klf4 preserves microglial and neuronal cells identities, while reducing neuroinflammation and neuronal apoptosis. Localized brain treatment with AAV-OSK enhances cognitive function, neuronal health, Aβ plaque clearance, microglial activity, and myelin integrity in early- and late-stage AD mouse models. Reduced representation bisulfite sequencing (RRBS) analysis indicated that these therapeutic benefits require DNA demethylation during reprogramming. Furthermore, this brain reprogramming approach also improves osteogenesis in AD-affected bone tissue. These findings suggest that reprogramming brain tissue can unlock youthful epigenetic information through DNA demethylation offering a novel strategy to improve both brain and extracerebral organ health in AD individuals.

ORGANISM(S): Mus musculus

PROVIDER: GSE288182 | GEO | 2026/08/12

REPOSITORIES: GEO

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Project description:Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by the buildup of amyloid-β and tau protein tangles. Alcohol use has been identified as a risk factor for AD; however, the molecular mechanisms underlying this potential causal link remain elusive. An emerging area of research focuses on the role of microglia, the brain's innate immune cells, in AD pathogenesis, with evidence suggesting that alcohol exposure may prime microglia to exhibit an exaggerated immune response when they are subsequently exposed to proinflammatory stimuli. We used a single 10-day chronic-plus-binge alcohol exposure model in male and female C57BL/J mice aged 8- to 10-weeks old. One month later, tauopathy was induced via adenoviral vector (AAV)-mediated overexpression of h-p301L tau. After 2.5 months, the mice underwent behavioral and cognitive testing. Two weeks later, microglia were collected using fluorescence-activated cell sorting (FACS) and processed for unbiased mass spectrometry and deep proteomic analysis to determine the molecular pathways related to microglial reactivity. Microglia from mice exposed to alcohol in young adulthood exhibited a blunted immune response when challenged with AAV-mediated delivery and accumulation of human tau later in life. This was characterized by decreased expression of MHC II- and interferon-associated proteins and bioinformatic prediction of inhibited inflammation-related pathways in the absence of gross histological, behavioral, or cognitive deficits. These results demonstrate unique, temporally specific microglial reactivity to tau that is modulated by early life alcohol exposure, implicating a microglial response that could negatively affect the mechanisms necessary for tau clearance and potentially exacerbate tau pathogenesis. This study provides novel insights into the long-term effects of early alcohol exposure on microglial function and the complexity of context-dependent microglial involvement in tau pathology. Consideration of early life environmental factors is critical for understanding and potentially mitigating the risk of neurodegenerative diseases, such as AD.

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Local brain reprogramming mitigates Alzheimer's disease and associated bone loss

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