Prolactin deficiency drives diabetes-associated cognitive dysfunction by inducing microglia-mediated synaptic loss

Area of Science:

• Neuroendocrinology
• Metabolic disorders
• Cognitive neuroscience

Background:

• Diabetes-associated cognitive dysfunction involves early hippocampal synaptic loss.
• Hormones, particularly pituitary hormones, play a role in synaptic regulation.
• The relationship between pituitary hormones and cognitive decline in diabetes requires further investigation.

Purpose of the Study:

• To explore the association between pituitary hormones and cognitive decline in type 2 diabetes (T2DM).
• To investigate the role of prolactin (PRL) in diabetes-related cognitive impairment and hippocampal pathology.

Main Methods:

• Clinical study of 744 T2DM patients with assessments of pituitary hormones, cognition, and MRI.
• Diabetic mouse models (HFD-fed) with dynamic diet interventions.
• Assessment of cognitive performance and hippocampal pathology in knockout mice (PRL, neuronal PRLR, microglial PRLR) and PRL-infused mice.

Main Results:

• Decreased PRL levels correlate with cognitive impairment and hippocampal damage in T2DM patients.
• In diabetic mice, reduced PRL precedes synaptic loss and cognitive decline.
• Microglial PRL receptor (PRLR) knockout, not neuronal, caused synaptic loss and cognitive impairment.
• PRL infusion mitigated microglial-mediated synaptic loss and improved cognitive function in diabetic mice.

Conclusions:

• Reduced prolactin (PRL) levels contribute to cognitive dysfunction and hippocampal synaptic loss in T2DM.
• The mechanism involves increased microglial-mediated synapse engulfment due to decreased PRL.
• Restoring PRL levels shows therapeutic potential for cognitive deficits and synaptic damage in diabetes.