Major depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimer's disease (AD). Despite both diseases having a robust genetic com Show more
Major depression (MD) is the most prevalent psychiatric disease in the population and is considered a prodromal stage of the Alzheimer's disease (AD). Despite both diseases having a robust genetic component, the common transcriptomic signature remains unknown. We investigated the cognitive and emotional behavioural responses in 3- and 6-month-old APP/PSEN1-Tg mice, before β-amyloid plaques were detected. We studied the genetic and pathway deregulation in the prefrontal cortex, striatum, hippocampus and amygdala of mice at both ages, using transcriptomic and functional data analysis. We found that depressive-like and anxiety-like behaviours, as well as memory impairments, are already present at 3-month-old APP/PSEN1-Tg mutant mice together with the deregulation of several genes, such as Ciart, Grin3b, Nr1d1 and Mc4r, and other genes including components of the circadian rhythms, electron transport chain and neurotransmission in all brain areas. Extending these results to human data performing GSEA analysis using DisGeNET database, it provides translational support for common deregulated gene sets related to MD and AD. The present study sheds light on the shared genetic bases between MD and AD, based on a comprehensive characterization from the behavioural to transcriptomic level. These findings suggest that late MD could be an early manifestation of AD. Show less
In the presence of a Wnt signal beta-catenin is spared from proteasomal degradation through a complex mechanism involving GSK3beta, resulting in the transcription of Wnt target genes. In this study we Show more
In the presence of a Wnt signal beta-catenin is spared from proteasomal degradation through a complex mechanism involving GSK3beta, resulting in the transcription of Wnt target genes. In this study we have explored whether GSK3alpha, a related isoform, can also regulate nuclear beta-catenin levels and whether this and the tau-directed kinase activity of GSK3alpha are modulated by Wnt. GSK3alpha or GSK3beta and their substrates, beta-catenin and tau, were transiently expressed in mammalian cells. Immunoblotting revealed that GSK3alpha reduces nuclear levels of beta-catenin, whilst reporter gene assays demonstrated that GSK3alpha inhibits beta-catenin-directed Tcf/Lef-dependent transcription. Moreover, activation of the Wnt pathway was found to attenuate both the beta-catenin- and the tau-directed kinase activities of GSK3alpha and GSK3beta. By immunoprecipitation we also found that axin-1, the beta-catenin destruction complex scaffold protein, binds GSK3alpha. In the light of these findings GSK3alpha warrants further investigation regarding its involvement in Wnt signalling and tauopathies such as Alzheimer's disease. Show less