RESUMEN
Blood-borne factors regulate adult hippocampal neurogenesis and cognition in mammals. We report that elevating circulating unacylated-ghrelin (UAG), using both pharmacological and genetic methods, reduced hippocampal neurogenesis and plasticity in mice. Spatial memory impairments observed in ghrelin-O-acyl transferase-null (GOAT-/-) mice that lack acyl-ghrelin (AG) but have high levels of UAG were rescued by acyl-ghrelin. Acyl-ghrelin-mediated neurogenesis in vitro was dependent on non-cell-autonomous BDNF signaling that was inhibited by UAG. These findings suggest that post-translational acylation of ghrelin is important to neurogenesis and memory in mice. To determine relevance in humans, we analyzed circulating AG:UAG in Parkinson disease (PD) patients diagnosed with dementia (PDD), cognitively intact PD patients, and controls. Notably, plasma AG:UAG was only reduced in PDD. Hippocampal ghrelin-receptor expression remained unchanged; however, GOAT+ cell number was reduced in PDD. We identify UAG as a regulator of hippocampal-dependent plasticity and spatial memory and AG:UAG as a putative circulating diagnostic biomarker of dementia.
Asunto(s)
Aciltransferasas/genética , Ghrelina/análogos & derivados , Ghrelina/genética , Hipocampo/metabolismo , Proteínas de la Membrana/genética , Enfermedad de Parkinson/genética , Parálisis Supranuclear Progresiva/genética , Aciltransferasas/deficiencia , Animales , Factor Neurotrófico Derivado del Encéfalo/genética , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Cognición/fisiología , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Ghrelina/metabolismo , Hipocampo/patología , Humanos , Masculino , Proteínas de la Membrana/deficiencia , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neurogénesis/genética , Plasticidad Neuronal/genética , Neuronas/metabolismo , Neuronas/patología , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Cultivo Primario de Células , Ratas , Transducción de Señal , Memoria Espacial/fisiología , Parálisis Supranuclear Progresiva/metabolismo , Parálisis Supranuclear Progresiva/patologíaRESUMEN
BACKGROUND: Urate and homocysteine are potential biomarkers for disease progression in Parkinson's disease (PD). Baseline serum urate concentration has been shown to predict motor but not cognitive decline. The relationship between serum homocysteine concentration and cognitive and motor impairment is unknown. OBJECTIVES: The aim of this study was to examine the association between baseline serum urate and homocysteine, and prospective measures of disease progression and cognition over 54 months in early PD. METHODS: 154 newly diagnosed PD participants and 99 age-matched controls completed a schedule of assessments at baseline, 18, 36 and 54 months. The Movement Disorders Society Unified Parkinson's Disease Scale Part III (MDS-UPDRS III) was used to assess motor severity. The Montreal Cognitive Assessment (MoCA) was used to assess global cognition. Serum samples drawn at baseline were analysed for urate, homocysteine, red cell folate and vitamin B12 concentrations. RESULTS: Baseline urate was 331.4±83.8 and 302.7±78.0µmol/L for control and PD participants, respectively (pâ=â0.015). Baseline homocysteine was 9.6±3.3 and 11.1±3.8µmol/L for controls and PD participants, respectively (pâ<â0.01). Linear mixed effects modelling showed that lower baseline urate (ß=â0.02, pâ<â0.001) and higher homocysteine (ß=â0.29, pâ<â0.05) predicted decline in motor function. Only higher homocysteine concentrations at baseline, however, predicted declining MoCA scores over 54 months (ß=â0.11, pâ<â0.01). CONCLUSIONS: Lower serum urate concentration is associated with worsening motor function; while higher homocysteine concentration is associated with change in motor function and cognitive decline. Therefore, urate and homocysteine may be suitable biomarkers for predicting motor and cognitive decline in early PD.
