Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline
Little, Karis (Queen's University Belfast)
Singh, Aditi (Queen's University Belfast)
Del Marco, Angel ![ORCID Identifier](/img/uab/orcid.ico)
(Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz)
Llorián-Salvador, María ![ORCID Identifier](/img/uab/orcid.ico)
(Hospital Universitari Vall d'Hebron)
Vargas-Soria, Maria (Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz)
Turch-Anguera, Mireia ![ORCID Identifier](/img/uab/orcid.ico)
(Hospital Universitari Vall d'Hebron)
Solé Piñol, Montserrat
(Hospital Universitari Vall d'Hebron)
Bakker, Noëlle (Amsterdam UMC location University)
Scullion, Sarah (Queen's University Belfast)
Comella i Carnicé, Joan Xavier 1963-
(Hospital Universitari Vall d'Hebron)
Klaassen, Ingeborg
(Amsterdam UMC location University of Amsterdam)
Simó Canonge, Rafael
(Hospital Universitari Vall d'Hebron)
Garcia-Alloza, Monica
(Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz)
Tiwari, Vijay K.
(Odense University Hospital (Dinamarca))
Stitt, Alan W.
(Queen's University Belfast)
Universitat Autònoma de Barcelona
Date: |
2023 |
Abstract: |
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. 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. 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. 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. The single-cell sequencing data that supports this study are available at GEO accession GSE217665 (). The online version contains peer-reviewed but unedited supplementary material available at 10. 1007/s00125-023-05935-2. |
Rights: |
Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. ![Creative Commons](/img/licenses/by.ico) |
Language: |
Anglès |
Document: |
Article ; recerca ; Versió publicada |
Subject: |
Cognitive decline ;
Cortex ;
Diabetes ;
Metabolism ;
Neuroscience ;
Neurovascular unit |
Published in: |
Diabetologia, Vol. 66 (june 2023) , p. 1557-1575, ISSN 1432-0428 |
DOI: 10.1007/s00125-023-05935-2
PMID: 37351595
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Record created 2023-09-13, last modified 2024-05-22