Disruption of cortical cell type composition and function underlies diabetes-associated cognitive decline

Area of Science:

• Neuroscience
• Genomics
• Metabolic disorders

Background:

• Type 2 diabetes (T2D) is linked to cognitive decline, but the underlying molecular mechanisms in the brain remain unclear.
• Understanding diabetes-induced changes in the cerebral cortex is crucial for identifying new therapeutic strategies.

Purpose of the Study:

• To investigate cell-specific gene expression changes and alterations in cell composition in the cerebral cortex of a mouse model of T2D.
• To validate scRNA-seq findings and assess their impact on the neurovascular unit (NVU), behavior, and cognition.
• To confirm findings in human post-mortem brain samples.

Main Methods:

• Single-cell transcriptomic sequencing (scRNA-seq) on mouse cerebral cortex.
• Immunohistochemistry and metabolic assessments.
• Behavioral tests (Morris water maze, novel object discrimination).
• Validation in human post-mortem brain tissues.

Main Results:

• T2D mice exhibited memory deficits, dysfunctional NVU, and cerebral atrophy.
• scRNA-seq identified altered cell populations (neurons, glia, microglia) and disrupted gene expression related to metabolism and neuronal maturation in T2D mice.
• Findings were validated in human T2D brain samples, showing metabolic and synaptic gene disruptions in NVU cells and reduced vascular density.

Conclusions:

• Diabetes induces significant disruptions in the cellular and molecular structure of the cerebral cortex.
• These alterations provide a molecular basis for progressive cognitive decline associated with T2D.
• The study highlights potential therapeutic targets within the cerebral cortex for managing diabetes-related cognitive impairment.