Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade

Molecular Neurodegeneration

  ^{1    2    3    4    5    5    5    6    6    7    8    9    1,10} 

[1] 0000 0004 1757 1969, grid.8158.4, Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95125, Catania, Italy;0000 0004 1757 1969, grid.8158.4, Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, 95125, Catania, Italy;Oasi Research Institute-IRCCS, 94018, Troina, Italy;0000 0004 1936 8796, grid.430387.b, Department of Pharmacology, Physiology and Neuroscience, Rutgers University, Newark, NJ, USA;0000000419368729, grid.21729.3f, Department of Medicine, Columbia University, 10032, New York, NY, USA;Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, 630 West 168th Street, P&S 12-420D, 10032, New York, NY, USA;Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, 630 West 168th Street, P&S 12-420D, 10032, New York, NY, USA;0000 0001 0481 6099, grid.5012.6, Faculty of Psychology and Neuroscience, Maastricht University, 6229, Maastricht, Netherlands;Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, 630 West 168th Street, P&S 12-420D, 10032, New York, NY, USA;0000 0001 2151 3065, grid.5606.5, Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, 16132, Genoa, Italy;Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, 630 West 168th Street, P&S 12-420D, 10032, New York, NY, USA;0000 0001 2151 3065, grid.5606.5, DiMi Department of Internal Medicine and Medical Specialties, University of Genoa, 16132, Genoa, Italy;Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, 630 West 168th Street, P&S 12-420D, 10032, New York, NY, USA;0000 0001 2322 1832, grid.260914.8, Department of Life Sciences, New York Institute of Technology, Northern Boulevard P.O. Box 8000, Theobald Science Center, room 425, 11568, Old Westbury, NY, USA;Taub Institute for Research on Alzheimer’s Disease and the Aging Brain, 630 West 168th Street, P&S 12-420D, 10032, New York, NY, USA;0000000419368729, grid.21729.3f, Department of Medicine, Columbia University, 10032, New York, NY, USA;0000000419368729, grid.21729.3f, Department of Pathology and Cell Biology, Columbia University, 10032, New York, NY, USA;

关键词: Tau oligomers;    Nitric oxide;    Soluble guanylyl cyclase;    PDE5;    Protein kinase G;    CREB;    Memory;    Alzheimer’s disease;   

DOI  :  10.1186/s13024-019-0326-4

来源: publisher

【 摘 要 】

BackgroundSoluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer’s disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown.MethodsThis work used a combination of biochemical, electrophysiological and behavioral techniques. Biochemical methods included analysis of phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, histone acetylation, and expression immediate early genes c-Fos and Arc. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated both short-term spatial memory and associative memory. These phenomena were examined following oTau elevation.ResultsLevels of phospho-CREB, histone 3 acetylation at lysine 27, and immediate early genes c-Fos and Arc, were found to be reduced after oTau elevation during memory formation. These findings led us to explore whether up-regulation of various components of the nitric oxide (NO) signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of plasticity, memory, and CREB phosphorylation. The increase of NO levels protected against oTau-induced impairment of LTP through activation of soluble guanylyl cyclase. Similarly, the elevation of cGMP levels and stimulation of the cGMP-dependent protein kinases (PKG) re-established normal LTP after exposure to oTau. Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 (PDE5), rescued oTau-induced LTP reduction. These findings could be extrapolated to memory because PKG activation and PDE5 inhibition rescued oTau-induced memory impairment. Finally, PDE5 inhibition re-established normal elevation of CREB phosphorylation and cGMP levels after memory induction in the presence of oTau.ConclusionsUp-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions.

【 授权许可】

CC BY