One of the traditional treatments in Alzheimer's disease (AD) is administration of memantine, the NMDA receptor antagonist. However, the molecular mechanism of the complex memantine action and the impact on the hippocampal proteome in humans is unknown. In this study, hippocampal proteins extracted from formalin-fixed paraffin-embedded post mortem tissues obtained from healthy donors (n = 15), AD patients not treated with memantine (n = 11), and AD patients treated with memantine (n = 8) were investigated using tandem mass tag (TMT)-based quantitative proteomics. Memantine medication induced subtle but distinct changes in the hippocampal proteome in AD patients. Although it did not prevent the metabolic and physiologic decline associated with AD pathology, memantine administration upregulated several mitochondrially encoded proteins and mitigated the proteomic pattern of activated phagocytes. Furthermore, memantine specifically enhanced the expression of postsynaptic glutamatergic and GABAergic receptors and components of the respective pathways without affecting presynaptic proteome. This suggests that memantine treatment in AD patients not only alleviates excitotoxic stress by inhibiting NMDA receptor activity, but also triggers broader adaptations in the synaptic signaling and plasticity.

3rd Faculty of Medicine Charles University Ruska 87 Prague Czech Republic

Biomedical Research Centre University Hospital Hradec Kralove Hradec Kralove Czech Republic

Clinic of Neurology 3rd Faculty of Medicine and Thomayer Hospital Prague Czech Republic

Department of Pathology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pathology and Molecular Medicine 3rd Faculty of Medicine Charles University and Thomayer University Hospital Prague Czech Republic

Department of Pathology Military University Hospital Prague Prague Czech Republic

Institute of Experimental Medicine of the Czech Academy of Sciences Prague Czech Republic

National Institute of Mental Health Klecany Czech Republic

The Fingerland Department of Pathology University Hospital Hradec Kralove Hradec Kralove Czech Republic

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