دورية أكاديمية
Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline
| العنوان: | Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline |
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| المؤلفون: | Little, K., Marco delgado, Ángel José del, Llorián-Salvador, M., Vargas Soria, María, Turch-Anguera, M., Solé, M., Bakker, N., Scullion, S., Comella, J.X., Klaassen, I., Simó, R., García Alloza, Mónica, Tiwari, V.K., Stitt, A.W. |
| المساهمون: | Biomedicina, Biotecnología y Salud Pública |
| المصدر: | Diabetologia - Vol.66 n.8 pp.1557-1575 |
| بيانات النشر: | Springer |
| سنة النشر: | 2024 |
| المجموعة: | RODIN - Repositorio de Objetos de Docencia e Investigación de la Universidad de Cádiz |
| مصطلحات موضوعية: | Cognitive decline, Cortex, Metabolism, Diabetes, Neuroscience, Neurovascular unit |
| الوصف: | Aims/hypothesis Type 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remains obscure. Deciphering diabetes-linked molecular mechanisms in cells of the cerebral cortex could uncover novel therapeutic targets. Methods Single-cell transcriptomic sequencing (scRNA-seq) was conducted on the cerebral cortex in a mouse model of type 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cell subpopulations and alterations in cell type composition. Immunohistochemistry and metabolic assessment were used to validate the fndings from scRNA-seq and to investigate whether these cell-specifc dysfunctions impact the neurovascular unit (NVU). Furthermore, the behavioural and cognitive alterations related to these dysfunctions in db/db mice were assessed via Morris water maze and novel object discrimination tests. Finally, results were validated in post-mortem sections and protein isolates from individuals with type 2 diabetes. Results Compared with non-diabetic control mice, the db/db mice demonstrated disrupted brain function as revealed by losses in episodic and spatial memory and this occurred concomitantly with dysfunctional NVU, neuronal circuitry and cerebral atrophy. scRNA-seq of db/db mouse cerebral cortex revealed cell population changes in neurons, glia and microglia linked to functional regulatory disruption including neuronal maturation and altered metabolism. These changes were validated through immunohistochemistry and protein expression analysis not just in the db/db mouse cerebral cortex but also in postmortem sections and protein isolates from individuals with type 2 diabetes (74.3 ± 5.5 years) compared with non-diabetic control individuals (87.0 ± 8.5 years). Furthermore, metabolic and synaptic gene disruptions were evident in cortical NVU cell populations and associated with a decrease in vascular density. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 1432-0428 |
| العلاقة: | info:eu-repo/grantAgreement/EC/H2020/847749/EU; http://hdl.handle.net/10498/31423Test |
| DOI: | 10.1007/s00125-023-05935-2 |
| الإتاحة: | https://doi.org/10.1007/s00125-023-05935-2Test http://hdl.handle.net/10498/31423Test |
| حقوق: | Atribución 4.0 Internacional ; http://creativecommons.org/licenses/by/4.0Test/ ; open access |
| رقم الانضمام: | edsbas.A6969C8F |
| قاعدة البيانات: | BASE |
| تدمد: | 14320428 |
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| DOI: | 10.1007/s00125-023-05935-2 |