Angeles Almeida

Parkinson’s disease (PD) is characterized by oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, for which effective treatments remain unavailable. Here, we report CL0179, a fungal-derived decahydrofluorene alkaloid with antioxidant-associated neuroprotective properties, and evaluate its effects across cellular and animal PD models. CL0179 exhibited a favorable safety profile and protected SHSY5Y against 6-hydroxydopamine- (6-OHDA), rotenone-, and 1-Methyl-4-phenylpyridinium-iodide (MPP⁺)-induced neurotoxicity by preserving mitochondrial membrane potential and network integrity. Transcriptomic analyses revealed selective restoration of gene-expression programs associated with oxidative phosphorylation, mitochondrial bioenergetics, and stress adaptation disrupted by MPP⁺. CL0179 also enhanced SIRT1 activity under MPP⁺ stress, whereas pharmacological SIRT1 inhibition partially attenuated protection of mitochondrial membrane potential and cell viability. In LRRK2-G2019S astrocytes, CL0179 reduced ROS and α-synuclein accumulation and restored mitochondrial organization, while in human dopaminergic neurons, it attenuated toxin-induced mitochondrial depolarization and preserved neuronal architecture. To overcome the low production of CL0179, we generated the structurally related analogue CL0670. Both compounds crossed the blood–brain barrier and protected mouse primary cortical neurons, while CL0670 improved motor deficits in a 6-OHDA mouse model. Collectively, these compounds promote mitochondrial resilience and stress-adaptive neuroprotection, supporting their potential for PD and related neurodegenerative disorders.

Perinatal failure in the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis causes impaired body growth and central and autonomous neurodevelopmental disorders. However, whether a primary neurodevelopmental disorder causes organ misinnervation as a contributing factor in growth retardation is elusive. To interrogate this, here we generated a late embryonic neural-specific cdc20 homolog 1 (Cdh1) knockout mouse model, which exhibited a primary delay in early postnatal brain development. These mice displayed an intact GH-releasing hormone (GHRH)-GH-hepatic GH receptor (GHR) pathway despite a body growth retardation that could be reversed by IGF-1 administration in the early postnatal life. Mechanistically, liver sympathetic misinnervation impaired signal transducers and activators of transcription 5 (STAT5) phosphorylation, required for liver IGF-1 biosynthesis and release. We also report decreased blood levels of IGF-1 in a patient harboring a pathogenic mutation in Cdh1 that causes neurodevelopmental and growth delay. Taken together, these findings demonstrate that a primary neurodevelopmental defect disrupts sympathetic hepatic innervation, leading to a GH-independent growth retardation, thus establishing a positive feedback loop that propagates the disease presentation.

Astrocytes, the most abundant glial cell type in the central nervous system, have traditionally been viewed from the perspective of metabolic support, particularly supplying neurons with lactate via glycolysis. This view has focused heavily on glucose metabolism as the primary mode of sustaining neuronal function. However, recent research challenges this paradigm by positioning astrocytes as dynamic metabolic hubs that actively engage in lipid metabolism, especially mitochondrial fatty acid β-oxidation. Far from serving solely as an energy source, fatty acid ß-oxidation in astrocytes orchestrates reactive oxygen species-mediated signaling pathways that modulate neuron-glia communication and cognitive outcomes. This review integrates recent advances on astrocytic fatty acid ß-oxidation and ketogenesis, alongside other metabolic pathways converging on reactive oxygen species dynamics, including cholesterol metabolism and peroxisomal β-oxidation. In reframing astrocytic metabolism from energy provision to signaling, we propose new directions for understanding central nervous system function and dysfunction.

La enfermedad de Alzheimer es un trastorno neurodegenerativo progresivo, caracterizado por la disfunción cognitiva, cuya prevalencia aumenta diariamente. Sus mecanismos fisiopatológicos descritos incluyen la acumulación de beta-amiloide y el estrés oxidativo. En este trabajo estudiamos la relación de dichos elementos con la proteína Bmal1, elemento del reloj circadiano central que puede alterar el desarrollo de enfermedades neurodegenerativas. Asimismo, se probaron compuestos alcaloides pirrocidínicos con actividad antioxidante y posible potencial neuroprotector de la empresa Instituto Biomar S.A. En cultivos neuronales tratados con beta-amiloide se estudió la variación de Bmal1 en medios con y sin antioxidantes mediante Western-Blot, observándose que en medio con antioxidantes se mantuvieron sus niveles. En estos cultivos, el tratamiento con los compuestos experimentales CL0179 y CL0670 logró mantener los niveles de Bmal1. Además, se cuantificó la apoptosis mediante caspasa-3, evidenciando su disminución en los cultivos tratados. Estos resultados esclarecen la relación beta-amiloide, Bmal1 y estrés oxidativo. Como indica bibliografía anterior, el beta-amiloide disminuye los niveles de Bmal1 en cultivos neuronales y el estrés oxidativo puede ser determinante en la muerte neuronal influenciada por acumulación de beta-amiloide. Los compuestos testados muestran actividad neuroprotectora, posiblemente mediada por el mantenimiento de Bmal1, abriendo una vía para el desarrollo de nuevos tratamientos contra patologías neurodegenerativas.

Glycolysis is primarily involved in ATP production but also modulates oxidative stress. Chronic alcohol consumption is correlated with an increased incidence of multiple diseases, including cancer and neurodegenerative diseases (NDDs), though the underlying mechanisms remain unclear. Guided by a literature review and bioinformatics analysis, we evaluated the expression of 22 genes encoding various isoforms of seven glycolytic enzymes (GEs) in the peripheral blood of patients with alcohol use disorder (AUD), individuals with acute alcohol consumption (AAC), and their respective control groups using qPCR. In parallel, we evaluated the expression of selected genes coding for GEs linked to NDDs, as well as astrocytic markers in primary mouse astrocyte cultures exposed to ethanol. Thirteen GE-related genes, including non-canonical isoforms, were significantly dysregulated in AUD patients; notably, eight of these genes showed similar alterations in individuals with AAC. Several enzymes encoded by these genes are known to be regulated by oxidative stress. Ethanol-exposed astrocytes also showed altered expression of glycolytic genes associated with NDDs and astrocyte function. These findings indicate that glycolytic dysregulation is driven by ethanol intake, regardless of exposure duration or organic damage, highlighting a link between ethanol-driven redox imbalance and glycolytic remodeling, which could contribute to organ damage.

This editorial challenges the long‐held neuron‐centered view of brain metabolism, relying on ample evidence that it is a cooperative, multicellular process. Astrocytes, oligodendrocytes, and other glia play active roles providing lactate, antioxidant support, and substrate shuttles that fuel neuronal function and memory. Despite mounting data, some critics persist in refuting intercellular metabolic exchange, often guided more by entrenched creeds than concrete evidence, slowing constructive, hypothesis‐driven discourse and delaying clinical and neuroprotective advances. The authors call for a rigorous research agenda: cell‐type‐specific manipulations, advanced biosensors, imaging and biomarkers, and integration with behavior and electrophysiology. They urge redirecting focus from outdated dogma to physiology‐driven exploration of glia–neuron metabolic partnerships. image

Retinal detachment (RD) separates the retina from the retinal epithelium, causing photoreceptor apoptosis and irreversible vision loss. Even with successful surgical reattachment, complete visual recovery is not guaranteed. The TP53 Arg72Pro polymorphism, implicated in apoptosis, has emerged as a potential predictor of RD outcomes. We investigated the impact of the Arg72Pro polymorphism on retinal neurodegeneration and functional recovery in patients. The underlying mechanisms were analyzed in a humanized TP53 Arg72Pro RD mouse model. In a cohort of 180 patients, carriers of the Pro allele exhibited decreased apoptotic gene expression and improved visual recovery. Complementary findings in mice revealed that the Pro variant preserved photoreceptor integrity and reduced apoptosis rates following RD. Our findings highlight the potential of this TP53 polymorphism as a biomarker for RD outcomes and a tool for tailoring therapies. This study underscores the importance of integrating genetic profiling into personalized medicine approaches to improve recovery of RD patients’ visual outcomes.

Non-traumatic intracerebral hemorrhage (ICH) is one of the most devastating and disabling forms of stroke; however, there are no effective pharmacological therapies available following the insult. Angiogenesis appears as a key step to overcoming the damage and promoting functional recovery. In this context, endothelial progenitor cells (EPCs) mobilization improves oxidative stress and promotes neovascularization, which has been linked to beneficial outcomes following both ischemic and hemorrhagic stroke. The TNF-like weak inducer of apoptosis (TWEAK), binding to its receptor Fn14, has been suggested as an inducer of EPCs differentiation, viability and migration to the injury site in a model of myocardial infarction. Here, we have performed a proof-of-concept preclinical study in a rat model of ICH where we report that a 50 μg/kg dose of rat recombinant TWEAK (rTWEAK) promotes blood progenitor cells mobilization, mainly EPCs. As soon as 72 h post-injury, brain neovascularization, and, importantly, long-term hematoma reduction and improved functional recovery is reported. In contrast, a higher dose of 150 μg/kg blocked those beneficial outcomes. Therefore, a low dose of rTWEAK treatment promotes neovascularization and reduces brain damage in a rat model of ICH. Further clinical studies will be needed to demonstrate if rTWEAK could represent a new strategy to promote recovery following ICH.

The energy cost of neuronal activity is mainly sustained by glucose^1,2. However, in an apparent paradox, neurons modestly metabolize glucose through glycolysis^3–6, a circumstance that can be accounted for by the constant degradation of 6-phosphofructo-2-kinase–fructose-2,6-bisphosphatase-3 (PFKFB3)^3,7,8, a key glycolysis-promoting enzyme. To evaluate the in vivo physiological importance of this hypoglycolytic metabolism, here we genetically engineered mice with their neurons transformed into active glycolytic cells through Pfkfb3 expression. In vivo molecular, biochemical and metabolic flux analyses of these neurons revealed an accumulation of anomalous mitochondria, complex I disassembly, bioenergetic deficiency and mitochondrial redox stress. Notably, glycolysis-mediated nicotinamide adenine dinucleotide (NAD⁺) reduction impaired sirtuin-dependent autophagy. Furthermore, these mice displayed cognitive decline and a metabolic syndrome that was mimicked by confining Pfkfb3 expression to hypothalamic neurons. Neuron-specific genetic ablation of mitochondrial redox stress or brain NAD⁺ restoration corrected these behavioural alterations. Thus, the weak glycolytic nature of neurons is required to sustain higher-order organismal functions.