Seline, O. | Search bioRxiv

bioRxiv2026

Non-viral vasculogenic reprogramming restores cognition and mitigates pathology in Alzheimer's disease

Alzheimers Disease (AD) is characterized by progressive cognitive decline associated with amyloid-beta (A{beta}) plaques, neurofibrillaiy tangles, inflammation, synaptic loss, and profuse neuronal death. Accumulating evidence demonstrates that cerebrovascular impairment precedes the emergence of neuropathological hallmarks, implicating vascular dysfunction as an early contributor to AD onset and progression. We investigated a non-viral strategy to generate pro-vasculogenic fibroblasts by transiently overexpressing Et{upsilon}2, Foxc2, and Flii (EFF) as a potential cell-based therapy for neurovascular deficits in AD. To assess therapeutic potential, FFF-primc[d] fibroblasts were injected into a mouse model of AD (3xTg-AD) and wild-type controls via the intracerebroventricular (ICV) route, followed by cognitive assessments and subsequent brain tissue analyses. Our findings demonstrate that FFF-primed fibroblasts acquire vasculogenic properties, enhance cerebral blood flow (CBF), and alleviate spatial memory deficits in 3xTg-AD mice. Moreover, transplanted FFF-primed fibroblasts exhibited long-term survival, integrated into the brain vasculature, and promoted cortical vascular remodeling in the AD brain. Notably, ICV deployment of these cells is also correlated with reduced cortical amyloid-beta load, suggesting potential therapeutic benefits in reducing AD pathology. Transcriptomic analysis identified the activation of genes involved in fatty acid oxidation, such as Ppar, known for its anti-amyloidogenic and anti-inflammatory effects. Collectively, these findings highlight non- viral, reprogramming-based vasculogenic cell therapy as a promising strategy for Alzheimers disease, capable of alleviating cognitive decline and addressing AD pathology across cellular and tissue scales.

neuroscience↗

bioRxiv2026

Ketosis rescues frataxin deficiency and corrects disease phenotypes in an FRDA animal model

Friedreich ataxia (FRDA) is an autosomal recessive neurodegenerative disease caused by deficiency of the mitochondrial protein frataxin. Effective therapeutic options remain limited for FRDA. We previously demonstrated that frataxin regulates ketone body metabolism by modulating 3-Oxoacid CoA-Transferase 1 (OXCT1), the rate-limiting enzyme in ketone body catabolism. However, the mechanisms governing frataxin-dependent control of OXCT1 turnover as well as the contribution of frataxin deficiency-induced OXCT1 reduction to FRDA pathogenesis, have remained unclear. Here, we demonstrate that frataxin regulates OXCT1 protein turnover by inhibiting its ubiquitination and subsequent proteasomal degradation. The N-terminal 40 amino acids of frataxin mediate such events, as overexpression of this region alone blocks ubiquitin-proteasome system (UPS)-dependent OXCT1 degradation. To evaluate the impact of OXCT1 deficiency on FRDA phenotypes, we enhanced OXCT1 reduction by introducing a 50% OXCT1 knockout into frataxin-deficient KIKO mice (KIKO/OXCT1/-). While OXCT1 deficiency potentiates cell death in vitro in control and FRDA patient fibroblasts, further OXCT1 reduction in KIKO mice induces ketosis, increases frataxin levels, and improves neurobehavioral performance. The increase in frataxin does not reflect elevated FXN gene transcription but rather enhanced mitochondrial biogenesis, evidenced by increased biogenesis markers, restored mitochondrial morphology and size, and increased mitochondrial gene expression. Fasting-which promotes ketosis-similarly increases frataxin levels and mitochondrial biogenesis markers in older KIKO/OXCT1+/- mice. {beta}-hydroxybutyrate administration in FRDA iPSC-derived cardiomyocytes elevates frataxin levels and mitochondrial biogenesis markers, further supporting the beneficial effect of ketosis on frataxin expression and mitochondrial biogenesis. Collectively, our findings demonstrate that ketosis partially restores frataxin levels and ameliorates FRDA-related phenotypes, providing a potential therapeutic strategy for FRDA.

biochemistry↗