RESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-ß, 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-ß-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-ß. NFPS pretreatment prevented amyloid-ß-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-ß 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-ß-induced hippocampal damage.
Asunto(s)
Enfermedad de Alzheimer , Péptidos beta-Amiloides , Proteínas de Transporte de Glicina en la Membrana Plasmática , Hipocampo , Ratones Endogámicos C57BL , Fármacos Neuroprotectores , Animales , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/inducido químicamente , Enfermedad de Alzheimer/prevención & control , Péptidos beta-Amiloides/metabolismo , Masculino , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ratones , Hipocampo/metabolismo , Hipocampo/efectos de los fármacos , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Modelos Animales de Enfermedad , Sarcosina/análogos & derivados , Sarcosina/farmacología , Sarcosina/uso terapéutico , Neuroprotección/efectos de los fármacos , Neuroprotección/fisiologíaRESUMEN
L-3,4-dihydroxyphenylalanine (L-DOPA) is the main treatment for Parkinson's disease (PD) but with long term administration, motor complications such as dyskinesia are induced. Glycine transporter 1 (GlyT1) inhibition was shown to produce an anti-dyskinetic effect in parkinsonian rats and primates, coupled with an improvement in the anti-parkinsonian action of L-DOPA. The expression of GlyT1 in the brain in the dyskinetic state remains to be investigated. Here, we quantified the levels of GlyT1 across different brain regions using [3H]-NFPS in the presence of Org-25,935. Brain sections were chosen from sham-lesioned rats, L-DOPA-naïve 6-hydroxydopamine (6-OHDA)-lesioned rats and 6-OHDA-lesioned rats exhibiting mild or severe abnormal involuntary movements (AIMs). [3H]-NFPS binding decreased in the ipsilateral and contralateral thalamus, by 28% and 41%, in 6-OHDA-lesioned rats with severe AIMs compared to sham-lesioned animals (P < 0.01 and 0.001). [3H]-NFPS binding increased by 21% in the ipsilateral substantia nigra of 6-OHDA-lesioned rats with severe AIMs compared to 6-OHDA-lesioned rats with mild AIMs (P < 0.05). [3H]-NFPS binding was lower by 19% in the contralateral primary motor cortex and by 20% in the contralateral subthalamic nucleus of 6-OHDA-lesioned rats with mild AIMs animals compared to rats with severe AIMs (both P < 0.05). The severity of AIMs scores positively correlated with [3H]-NFPS binding in the ipsilateral substantia nigra (P < 0.05), ipsilateral entopeduncular nucleus (P < 0.05) and contralateral primary motor cortex (P < 0.05). These data provide an anatomical basis to explain the efficacy of GlyT1 inhibitors in dyskinesia in PD.
Asunto(s)
Encéfalo , Proteínas de Transporte de Glicina en la Membrana Plasmática , Oxidopamina , Sarcosina/análogos & derivados , Animales , Proteínas de Transporte de Glicina en la Membrana Plasmática/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Ratas , Masculino , Oxidopamina/farmacología , Encéfalo/metabolismo , Encéfalo/efectos de los fármacos , Trastornos Parkinsonianos/metabolismo , Ratas Sprague-Dawley , Modelos Animales de Enfermedad , Tritio , Lateralidad Funcional/fisiologíaRESUMEN
Withdrawal: Miran Yoo, Seong Muk Kim, Juho Lee, Hye-Ju Kim, Seong Jeong Park. "Glycine transporter 1 (GlyT1) is a novel therapeutic target for Alzheimer's disease" Alzheimer's & Dementia, Volume 18, Supplemental Issue 10. The above abstract, published online on 20th December 2022, on Wiley Online Library (https://alz-journals.onlinelibrary.wiley.com/doi/abs/10.1002/alz.064468) has been withdrawn by agreement between the authors, the Senior Director of Scientific Programs and Outreach, Claire Sexton, the Director of Scientific Programs at the Alzheimer's Association, Ozama Ismail, and John Wiley & Sons Inc. The abstract has been withdrawn at the authors' request because the authors did not have Amyloid Solution's authorization to publish the information contained in it.