RT journal article
T1 Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline
A1 Little, K.
A1 Marco Delgado, Ángel José del
A1 Llorián-Salvador, M.
A1 Vargas Soria, María
A1 Turch-Anguera, M.
A1 Solé, M.
A1 Bakker, N.
A1 Scullion, S.
A1 Comella, J.X.
A1 Klaassen, I.
A1 Simó, R.
A1 García Alloza, Mónica
A1 Tiwari, V.K.
A1 Stitt, A.W.
A2 BiomedicinaBiotecnología y Salud Pública
K1 Cognitive decline
K1 Cortex
K1 Metabolism
K1 Diabetes
K1 Neuroscience
K1 Neurovascular unit
AB Aims/hypothesis Type 2 diabetes is associated with increased risk of cognitive decline although the pathogenic basis for this remainsobscure. 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 oftype 2 diabetes (db/db mice) and in non-diabetic control mice in order to identify gene expression changes in distinct cellsubpopulations and alterations in cell type composition. Immunohistochemistry and metabolic assessment were used tovalidate the fndings from scRNA-seq and to investigate whether these cell-specifc dysfunctions impact the neurovascularunit (NVU). Furthermore, the behavioural and cognitive alterations related to these dysfunctions in db/db mice were assessedvia Morris water maze and novel object discrimination tests. Finally, results were validated in post-mortem sections andprotein 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 lossesin episodic and spatial memory and this occurred concomitantly with dysfunctional NVU, neuronal circuitry and cerebralatrophy. scRNA-seq of db/db mouse cerebral cortex revealed cell population changes in neurons, glia and microglia linkedto functional regulatory disruption including neuronal maturation and altered metabolism. These changes were validatedthrough 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-diabeticcontrol individuals (87.0 ± 8.5 years). Furthermore, metabolic and synaptic gene disruptions were evident in cortical NVUcell populations and associated with a decrease in vascular density.
PB Springer
SN 1432-0428
YR 2023
FD 2023
LK http://hdl.handle.net/10498/31423
UL http://hdl.handle.net/10498/31423
LA eng
DS Repositorio Institucional de la Universidad de Cádiz
RD 06-nov-2026