Memantine administration enhances glutamatergic and GABAergic pathways in human hippocampus of Alzheimer´s disease patients

Introduction: One of the traditional treatments in Alzheimer´s disease (AD) is an administration of memantine, the NMDA receptor antagonist. However, molecular mechanism of memantine complex action and the impact on hippocampal proteome in humans is unknown. Methods: Hippocampal proteins extracted from formalin-fixed paraffin embedded post mortem tissues obtained from healthy donors (n=15), AD patients not treated by memantine (n=11), and AD patients treated with memantine (n=8) were investigated using TMT-based quantitative proteomics. Results: The presented data show that memantine treatment has minor but characteristic effect on protein expression. Memantine medication selectively induced levels of several mitochondrially-encoded proteins, mitigated proteomic pattern of activated phagocytes, and enhanced expression of synaptic components involved in both inhibitory (GABA) and excitatory (glutamate) neurotransmission. Conclusions: The impact of memantine treatment exceeds its NMDA-blocking role. Memantine foremostly stimulates broad upregulation of proteins for which glutamate or GABA serve as ligands suggesting perturbation of glutamate/GABA signaling.