Venue: CARF
Organized by the CBMN (chimie et bioogie des membranes et des nano-objets)
Iker Bengoetxea
Institute of Neurosciences, University of Barcelona
Title
Context-dependent modulation of brain senescence by senolytics in mouse models of Alzheimer’s disease and accelerated ageing
Abstract
Our study investigates the role of cellular senescence in brain ageing and Alzheimer’s disease and evaluates senolytic therapeutic strategies. We analysed the impact of a senolytic treatment in two complementary mouse models: 5xFAD mice, representing pathological amyloid-driven senescence, and SAMP8 mice, modelling physiological ageing-associated senescence. Five-month-old mice received a chronic intermittent treatment for two months, and cognitive performance was assessed through behavioural tests of anxiety and recognition memory. Senescence-associated β-galactosidase, amyloid burden, lysosomal content, and glial phenotypes were analysed using immunohistochemistry and colorimetric imaging to characterise senescence markers and glial cell heterogeneity, as well as through ELISAs and RNAseq.
The senolytic treatment improved cognitive performance in both models, ameliorating both anxiety phenotypes and memory. In 5xFAD mice, treatment reduced amyloid plaque burden, lysosomal accumulation, and modulated microglial response in specific brain regions. In SAMP8 mice, it altered microglial and oligodendroglial phenotypes, indicating context-dependent effects on neuroinflammation. Our findings highlight senescence heterogeneity and support the therapeutic potential of senolytic strategies to mitigate cognitive decline. The use, in parallel, of two distinct brain senescence paradigms strengthens the translational potential of our findings.
Biosketch
PhD graduate in Pharmacology from the University of the Basque Country (UPV/EHU, Bilbao, Spain), he completed his doctoral training under the supervision of Dr. Rafael Rodríguez Puertas. Research focused on neurolipids, particularly the endocannabinoid system, in the context of dementia and cognitive impairment, particularly Alzheimer’s disease. During this period, he also completed a four-month international research stay at the Institut de Chimie & Biologie des Membranes & des Nano-objets (CBMN, Bordeaux, France), investigating how the membrane lipidome modulates ligand binding properties and activity of cannabinoid receptors. As a postdoctoral researcher, he is working under the supervision of Dr. Ana Guerrero in the Cell Biology Department at the University of Barcelona, affiliated with the Institute of Neurosciences (UBNeuro, María de Maeztu unit of excellence), a leading international centre in neuroscience research. In this setting, he is investigating the contribution of cellular senescence to the pathophysiology of Alzheimer’s disease, pursuing neurodegeneration research from a complementary perspective.
As a second-year postdoc, his contributions have resulted in 10 research articles, including 4 first-author papers from his doctoral research and different successful collaborative works, including publications in prestigious and high-impact journals such as Translational Neurodegeneration and the British Journal of Pharmacology.
Rafael Rodríguez Puertas
University of the Basque Country (UPV/EHU)
Title
Neurolipid-based therapies for dementia of the Alzheimer’s type and development of Imaging cellular brain lipotypes by mass spectrometry
Abstract
Our studies are analysing the signalling by neurolipids in Alzheimer’s type dementia for the development of new therapeutic strategies. The study identifies the cellular lipid specialization in the brain of the lipotypic profiles for neurons, astrocytes, oligodendrocytes, microglia, and choroid plexus, using mass spectrometry imaging (MSI) on purified cell cultures from rat brain. Next, we imaged with MSI different brain regions from rats, mice and human samples, collecting anatomically detailed maps of spectral lipidic profiles. Finally, we quantified in each anatomical map the presence of each cell type using its own spectral lipidic signature (lipotype). Our computational approach represents a novel methodology to study the anatomical distribution of cell lipotypes and its regulation in brain circuits without any labelling. Furthermore, we applied this method to both healthy and lesion-induced brain tissues, demonstrating its potential to track lipid changes in pathological conditions.
Biosketch
Dr. R. Rodríguez Puertas from the Department of Pharmacology at the University of the Basque Country (UPV/EHU) returned in late 1997 from a three-year postdoctoral stay at the Karolinska Institute (Stockholm). In 2001, he obtained a Ramón y Cajal position in the program’s first call. In 2011, he secured one of the first Permanent Research Professor positions at the University of the Basque Country through a competitive process and is accredited as a Full Research Professor. He has made significant scientific contributions to the study of neurochemistry in Alzheimer’s disease (AD) since his doctoral work (University of Cantabria, 1995). His research has been published in over 70 scientific papers. He has served as the principal investigator (PI) of research projects since founding the Neurochemistry and Neurodegeneration Group in 2003. His notable studies focus on neurotransmission alterations in AD patients and animal models and modulation by neurolipid system, pioneering in develop and application of mass spectrometry imaging (MSI) technology in neuropharmacology. PI of two patents currently being exploited by IMGPharma, a NEBT (New Technology-Based Company) arising from his group. Promising recent results with new patented treatments in animal models position the research group for impactful outcomes.