RESUMO
Recent imaging studies of amyloid and tau in cognitively normal elderly subjects imply that Alzheimer's pathology can be tolerated by the brain to some extent due to compensatory mechanisms operating at the cellular and synaptic levels. The present study investigated the effects of an allosteric inhibitor of phosphodiesterase-4D (PDE4D), known as BPN14770 (2-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetic Acid), on impairment of memory, dendritic structure, and synaptic proteins induced by bilateral microinjection of oligomeric amyloid beta (Aß 1-42 into the hippocampus of humanized PDE4D (hPDE4D) mice. The hPDE4D mice provide a unique and powerful genetic tool for assessing PDE4D target engagement. Behavioral studies showed that treatment with BPN14770 significantly improved memory acquisition and retrieval in the Morris water maze test and the percentage of alternations in the Y-maze test in the model of Aß impairment. Microinjection of oligomeric Aß 1-42 caused decreases in the number of dendrites, dendritic length, and spine density of pyramid neurons in the hippocampus. These changes were prevented by BPN14770 in a dose-dependent manner. Furthermore, molecular studies showed that BPN14770 prevented Aß-induced decreases in synaptophysin, postsynaptic density protein 95, phosphorylated cAMP-response element binding protein (CREB)/CREB, brain-derived neurotrophic factor, and nerve growth factor inducible protein levels in the hippocampus. The protective effects of BPN14770 against Aß-induced memory deficits, synaptic damage, and the alteration in the cAMP-meditated cell signaling cascade were blocked by H-89 (N-[2-(p-Bromocinnamylamino)ethyl]-5-isoquinolinesulfonamide dihydrochloride), an inhibitor of protein kinase A. These results suggest that BPN14770 may activate compensatory mechanisms that support synaptic health even with the onset of amyloid pathology in Alzheimer's disease. SIGNIFICANCE STATEMENT: This study demonstrates that a phosphodiesterase-4D allosteric inhibitor, BPN14770, protects against memory loss and neuronal atrophy induced by oligomeric Aß 1-42. The study provides useful insight into the potential role of compensatory mechanisms in Alzheimer's disease in a model of oligomeric Aß 1-42 neurotoxicity.
Assuntos
Peptídeos beta-Amiloides/toxicidade , Hipocampo/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/prevenção & controle , Fármacos Neuroprotetores/uso terapêutico , Fragmentos de Peptídeos/toxicidade , Inibidores da Fosfodiesterase 4/uso terapêutico , Regulação Alostérica/efeitos dos fármacos , Regulação Alostérica/fisiologia , Animais , Técnicas de Introdução de Genes , Hipocampo/patologia , Humanos , Transtornos da Memória/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Distribuição AleatóriaRESUMO
The study of vegetation phenology is of great significance for understanding global climate change. The Yellow River basin has a wide spatial range and a complex ecological environment. The phenological characteristics of forest and grassland need further clarification. Based on the MODIS-EVI data from 2000 to 2018, we extracted the phenology of forest and grassland in the Yellow River basin using piecewise logistic and double logistic phenological models with the corresponding curvature change extremum method and derivative method, respectively. The temporal and spatial variations of phenological parameters were analyzed. The start of growing season (SOS) was at 90-165 day of year (DOY), and gradually delayed from southeast to northwest. The increase of 100 m elevation delayed SOS 0.94 d, and the SOS of forest was earlier than that of grassland. The end of growing season (EOS) was at 270-315 DOY, which delayed from west to southeast. For every 100 m increase in altitude, the EOS advanced 0.63 d, with EOS of forest being later than that of grassland. The length of growing season (LOS) was 110-230 d, which shortened gradually from southeast to northwest. The LOS of forest was larger than that of grassland. During the study, SOS showed an advance trend from 2000 to 2018 with a rate of 4.1 d·(10 a)-1, and the proportion of spatial advance area was 73.2%. There was an obvious advance in the central part of the basin. EOS generally showed a significant postponement trend with a rate of 2.3 d·(10 a)-1, and the proportion of spatially delayed area was 63.4%, the phenological advance and delay of forest was less stronger than that of grassland. LOS showed a significant prolongation trend with a rate of 6.4 d·(10 a)-1, and the proportion of spatial extension was 71.8%. The piecewise Logistic and double Logistic phenological models and the corresponding curvature extremum method and derivative method were suitable for the extraction of natural vegetation in the Yellow River Basin. The overall LOS of forest and grassland showed a prolonging trend, which was shortened with the increases of altitude. The LOS of forest was longer than that of grassland in the study area.