Alzheimer’s disease (AD) is increasingly recognized as a metabolic disorder, in which brain insulin resistance and mitochondrial dysfunction represent early pathogenic events. Biliverdin reductase A (BVRA), a pleiotropic protein with different roles as reductase, S/TS/Y kinase, scaffold and intracellular shuttle, regulates insulin signaling and mitochondrial metabolism. Although reduced BVRA has been reported in obesity, type 2 diabetes, and AD, the mechanisms linking BVRA loss to impaired brain metabolic resilience remain to be addressed. We integrated experimental models and human biomarker approaches to define the metabolic consequences of BVRA loss across aging and AD. In wild-type and BVRA knockout mice, we assessed brain insulin signaling pathways, mitochondrial function (including respirometry-based profiling), biochemical readouts of neuronal bioenergetics, and cognitive outcomes under aging and metabolic stress conditions. In parallel, we quantified BVRA in neuronal-derived extracellular vesicles (nEVs) from Ctr subjects and AD patients and tested associations with cognitive performance and AD diagnosis. BVRA loss promoted defective insulin signaling, impaired pGSK3βS9 translocation into mitochondria, and reduced activity of mitochondrial respiratory complexes, converging on energy metabolism failure and exacerbated brain insulin resistance during aging and metabolic stress. In humans, reduced BVR-A levels in nEVs were significantly associated with cognitive decline and AD diagnosis. Collectively, these data support a role for BVRA as a molecular shuttle linking insulin signaling to mitochondrial function and cellular stress-response pathways. BVRA emerges as a critical mediator of brain metabolic resilience, whose loss accelerates insulin resistance, mitochondrial dysfunction, and cognitive deterioration. Targeting BVRA–dependent pathways may enable earlier diagnosis and more personalized therapeutic strategies in AD and related metabolic conditions.
Lanzillotta, S., Zulli, B., Sommella, V., Paolozzi, G., Picca, A., Calvani, R., Marzetti, E., Boccardi, V., Cecchetti, R., Paul, B. D., Mecocci, P., Tramutola, A., Di Domenico, F., Perluigi, M., Barone, E., Biliverdin reductase A and metabolic resilience in Alzheimer’s disease, Abstract de <<SFRR-E Annual Meeting 2026 “Redox Biology, Environmental Exposure and Lifestyle”>>, (Mainz, Germany, 03-05 June 2026 ), <<FREE RADICAL BIOLOGY & MEDICINE>>, 2026; 249 (Suppl 1): S16-S17. 10.1016/j.freeradbiomed.2026.05.075 [https://hdl.handle.net/10807/337717]
Biliverdin reductase A and metabolic resilience in Alzheimer’s disease
Calvani, Riccardo;Marzetti, Emanuele;
2026
Abstract
Alzheimer’s disease (AD) is increasingly recognized as a metabolic disorder, in which brain insulin resistance and mitochondrial dysfunction represent early pathogenic events. Biliverdin reductase A (BVRA), a pleiotropic protein with different roles as reductase, S/TS/Y kinase, scaffold and intracellular shuttle, regulates insulin signaling and mitochondrial metabolism. Although reduced BVRA has been reported in obesity, type 2 diabetes, and AD, the mechanisms linking BVRA loss to impaired brain metabolic resilience remain to be addressed. We integrated experimental models and human biomarker approaches to define the metabolic consequences of BVRA loss across aging and AD. In wild-type and BVRA knockout mice, we assessed brain insulin signaling pathways, mitochondrial function (including respirometry-based profiling), biochemical readouts of neuronal bioenergetics, and cognitive outcomes under aging and metabolic stress conditions. In parallel, we quantified BVRA in neuronal-derived extracellular vesicles (nEVs) from Ctr subjects and AD patients and tested associations with cognitive performance and AD diagnosis. BVRA loss promoted defective insulin signaling, impaired pGSK3βS9 translocation into mitochondria, and reduced activity of mitochondrial respiratory complexes, converging on energy metabolism failure and exacerbated brain insulin resistance during aging and metabolic stress. In humans, reduced BVR-A levels in nEVs were significantly associated with cognitive decline and AD diagnosis. Collectively, these data support a role for BVRA as a molecular shuttle linking insulin signaling to mitochondrial function and cellular stress-response pathways. BVRA emerges as a critical mediator of brain metabolic resilience, whose loss accelerates insulin resistance, mitochondrial dysfunction, and cognitive deterioration. Targeting BVRA–dependent pathways may enable earlier diagnosis and more personalized therapeutic strategies in AD and related metabolic conditions.
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