Abstract
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 findings from scRNA-seq and to investigate whether these cell-specific 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 post-mortem 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. Conclusions/interpretation: Taken together, our data reveal disruption in the cellular and molecular architecture of the cerebral cortex induced by diabetes, which can explain, at least in part, the basis for progressive cognitive decline in individuals with type 2 diabetes.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Diabetologia |
| Vol/bind | 66 |
| Udgave nummer | 8 |
| Sider (fra-til) | 1557-1575 |
| ISSN | 0012-186X |
| DOI | |
| Status | Udgivet - aug. 2023 |
Bibliografisk note
Funding Information:The authors wish to thank K. Harkin (Queen’s University Belfast) for assistance with single-cell dissociation experiments. The authors would also like to acknowledge the support provided by Genomics Core Technology Unit (GCTU), as well as resources and consultancy provided by High Performance Computational Services (Kelvin Cluster) team and the Advanced Imaging Core Technology Unit (AICTU), Queen’s University Belfast. The authors thank the Animal Facility of the University of Cadiz and its personnel for their help and support and thank Servicios Centrales de Investigacion en Biomedicina (SC-IBM) from Universidad de Cadiz for the resources and technical support. Schematics were created with BioRender.com.
Funding Information:
This work is supported by the RECOGNISED consortium grant (EU GA 847749) to MGA and AWS and by the Deutsche Forschungsgemeinschaft TI 799/1-3 and Novo Nordisk Foundation P3110103 grants to VKT. MLS is funded by Maria Zambrano fellowship from Spanish Ministry of Science, Innovation and Universities, funded by European Union ‘Next Generation EU’ (Universitat Autònoma de Barcelona). The study funders were not involved in the design of the study; the collection, analysis, and interpretation of data; writing the report; and did not impose any restrictions regarding the publication of the report.
Publisher Copyright:
© 2023, Crown.