PMID- 37351595 OWN - NLM STAT- MEDLINE DCOM- 20230705 LR - 20230821 IS - 1432-0428 (Electronic) IS - 0012-186X (Print) IS - 0012-186X (Linking) VI - 66 IP - 8 DP - 2023 Aug TI - Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline. PG - 1557-1575 LID - 10.1007/s00125-023-05935-2 [doi] AB - 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. DATA AVAILABILITY: The single-cell sequencing data that supports this study are available at GEO accession GSE217665 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE217665 ). CI - (c) 2023. Crown. FAU - Little, Karis AU - Little K AD - The Wellcome‑Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. FAU - Singh, Aditi AU - Singh A AD - The Wellcome‑Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. FAU - Del Marco, Angel AU - Del Marco A AUID- ORCID: 0000-0001-7911-2395 AD - Division of Physiology, School of Medicine, University of Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. FAU - Llorian-Salvador, Maria AU - Llorian-Salvador M AUID- ORCID: 0000-0002-1120-6579 AD - The Wellcome‑Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. AD - Department of Medicine, Universitat Autonoma de Barcelona (UAB), Barcelona, Spain. AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain. FAU - Vargas-Soria, Maria AU - Vargas-Soria M AD - Division of Physiology, School of Medicine, University of Cadiz, Cadiz, Spain. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. FAU - Turch-Anguera, Mireia AU - Turch-Anguera M AUID- ORCID: 0000-0002-1862-6285 AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain. AD - Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. AD - Departament de Bioquimica i Biologia Molecular i Institut de Neurociencies, Universitat Autonoma de Barcelona (UAB), Bellaterra, Spain. AD - Centro de Investigacion en Red en Enfermedades Neurodegenerativas (CIBERNED - ISCII), Madrid, Spain. FAU - Sole, Montse AU - Sole M AUID- ORCID: 0000-0003-4240-6562 AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain. AD - Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. AD - Departament de Bioquimica i Biologia Molecular i Institut de Neurociencies, Universitat Autonoma de Barcelona (UAB), Bellaterra, Spain. AD - Centro de Investigacion en Red en Enfermedades Neurodegenerativas (CIBERNED - ISCII), Madrid, Spain. FAU - Bakker, Noelle AU - Bakker N AD - Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands. FAU - Scullion, Sarah AU - Scullion S AD - The Wellcome‑Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. FAU - Comella, Joan X AU - Comella JX AUID- ORCID: 0000-0002-6218-0786 AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain. AD - Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Barcelona, Spain. AD - Departament de Bioquimica i Biologia Molecular i Institut de Neurociencies, Universitat Autonoma de Barcelona (UAB), Bellaterra, Spain. AD - Centro de Investigacion en Red en Enfermedades Neurodegenerativas (CIBERNED - ISCII), Madrid, Spain. FAU - Klaassen, Ingeborg AU - Klaassen I AUID- ORCID: 0000-0003-1695-9403 AD - Ocular Angiogenesis Group, Department of Ophthalmology, Amsterdam UMC location University of Amsterdam, Amsterdam, the Netherlands. FAU - Simo, Rafael AU - Simo R AUID- ORCID: 0000-0003-0475-3096 AD - Department of Medicine, Universitat Autonoma de Barcelona (UAB), Barcelona, Spain. AD - Diabetes and Metabolism Research Unit, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron University Hospital, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas (CIBERDEM-ISCIII), Madrid, Spain. FAU - Garcia-Alloza, Monica AU - Garcia-Alloza M AUID- ORCID: 0000-0003-1610-4114 AD - Division of Physiology, School of Medicine, University of Cadiz, Cadiz, Spain. monica.garcia@uca.es. AD - Instituto de Investigacion e Innovacion en Ciencias Biomedicas de la Provincia de Cadiz (INIBICA), Cadiz, Spain. monica.garcia@uca.es. FAU - Tiwari, Vijay K AU - Tiwari VK AUID- ORCID: 0000-0003-0292-6635 AD - The Wellcome‑Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. tiwari@health.sdu.dk. AD - Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark. tiwari@health.sdu.dk. AD - Danish Institute for Advanced Study (DIAS), Odense M, Denmark. tiwari@health.sdu.dk. AD - Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark. tiwari@health.sdu.dk. FAU - Stitt, Alan W AU - Stitt AW AUID- ORCID: 0000-0002-8647-9918 AD - The Wellcome‑Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry & Biomedical Science, Queen's University Belfast, Belfast, Northern Ireland, UK. a.stitt@qub.ac.uk. CN - RECOGNISED consortium LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230623 PL - Germany TA - Diabetologia JT - Diabetologia JID - 0006777 SB - IM MH - Mice MH - Animals MH - *Diabetes Mellitus, Type 2/complications MH - *Cognitive Dysfunction/drug therapy MH - Cerebral Cortex/metabolism MH - Disease Models, Animal PMC - PMC10317904 OTO - NOTNLM OT - Cognitive decline OT - Cortex OT - Diabetes OT - Metabolism OT - Neuroscience OT - Neurovascular unit EDAT- 2023/06/23 13:07 MHDA- 2023/07/05 06:42 PMCR- 2023/06/23 CRDT- 2023/06/23 11:04 PHST- 2022/12/12 00:00 [received] PHST- 2023/03/28 00:00 [accepted] PHST- 2023/07/05 06:42 [medline] PHST- 2023/06/23 13:07 [pubmed] PHST- 2023/06/23 11:04 [entrez] PHST- 2023/06/23 00:00 [pmc-release] AID - 10.1007/s00125-023-05935-2 [pii] AID - 5935 [pii] AID - 10.1007/s00125-023-05935-2 [doi] PST - ppublish SO - Diabetologia. 2023 Aug;66(8):1557-1575. doi: 10.1007/s00125-023-05935-2. Epub 2023 Jun 23.