A link between glycolysis and neurotransmission in Alzheimer's disease the role of gender and serine

Healthy aging is an ambitious aspiration of human population although neurodegenerative disorders, such as Alzheimer's disease (AD), strongly affect the quality of life. We investigated by an integrated multi-omics approach the alterations in molecular composition of post-mortem hippocampus samples of healthy persons and AD patients. Severe differences were apparent comparing control male and female cohorts in terms of up- and downregulated metabolic pathways. Considering the AD condition, a different mechanism of activation of NMDA receptors between genders is disclosed: in females it is mainly due to the upregulation of the serine metabolism (linked to the glycolytic pathway and generating the NMDA receptor co-agonist D-serine), while in males it is mainly due to the arginine metabolism. These results show how AD condition changes, and for some respects almost reverses, the proteomic and metabolomic profile peculiar to males and females, highlighting that different pathophysiological mechanisms are active in males and females