GlyT1 Inhibition by NFPS Promotes Neuroprotection in Amyloid-β-Induced Alzheimer's Disease Animal Model

Autor(es)

Oliveira-Lima, Onesia Cristina ; de Carvalho, Gustavo Almeida ; Assuncao, Leandro do Prado ; Bailao, Alexandre Melo ; Ulrich, Henning ; Marques, Bruno Lemes ; de Oliveira, Antonio Carlos Pinheiro ; Gomez, Renato Santiago ; Pinto, Mauro Cunha Xavier

• Tipo de documento: Artigo Científico
• Fonte: Neurochemical Research; v. 49, n. 9, p. 21-pg., 2024-06-18.

Resumo

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta, leading to N-methyl-D-aspartate (NMDA) receptor-dependent synaptic depression, spine elimination, and memory deficits. Glycine transporter type 1 (GlyT1) modulates glutamatergic neurotransmission via NMDA receptors (NMDAR), presenting a potential alternative therapeutic approach for AD. This study investigates the neuroprotective potential of GlyT1 inhibition in an amyloid-beta-induced AD mouse model. C57BL/6 mice were treated with N-[3-([1,1-Biphenyl]-4-yloxy)-3-(4-fluorophenyl)propyl]-N-methylglycine (NFPS), a GlyT1 inhibitor, 24 h prior to intrahippocampal injection of amyloid-beta. NFPS pretreatment prevented amyloid-beta-induced cognitive deficits in short-term and long-term memory, evidenced by novel object recognition and spatial memory tasks. Moreover, NFPS pretreatment curbed microglial activation, astrocytic reactivity, and subsequent neuronal damage from amyloid-beta injection. An extensive label-free quantitative UPLC-MSE proteomic analysis was performed on the hippocampi of mice treated with NFPS. In proteomics, KEGG enrichment analysis revealed increased in dopaminergic synapse, purine-containing compound biosynthetic process and long-term potentiation, and a reduction in Glucose catabolic process and glycolytic process pathways. The western blot analysis confirmed that NFPS treatment elevated BDNF levels, correlating with enhanced TRKB phosphorylation and mTOR activation. Moreover, NFPS treatment reduced the GluN2B expression after 6 h, which was associated with an increase on CaMKIV and CREB phosphorylation. Collectively, these findings demonstrate that GlyT1 inhibition by NFPS activates diverse neuroprotective pathways, enhancing long-term potentiation signaling and countering amyloid-beta-induced hippocampal damage. (AU)

• Processo FAPESP: 18/07366-4 - Receptores de purinas e cininas como alvos de estudo e intervenção terapêutica em doenças neurológicas
• Beneficiário: Alexander Henning Ulrich
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 18/08426-0 - Alcalóides indólicos, subprodutos do processamento de Maqui (Aristotelia chilensis) como aditivos alimentares no tratamento da Doença de Alzheimer
• Beneficiário: Alexander Henning Ulrich
• Modalidade de apoio: Auxílio à Pesquisa - Regular