| dc.description.abstracteng | Alzheimer’s disease (AD) is a neurodegenerative disease and the most common form of dementia. The number of AD cases increases exponentially every year.
Although AD has been investigated for a long time, the precise molecular mechanisms involved remain to be elucidated, especially at early stages of the pathology. Furthermore, a cure does not exist to date. The treatments currently available are administered too late and are only temporarily effective for certain dementia-associated symptoms. These difficulties to discover an effective treatment are probably due to the complexity of the pathological process. There is emerging evidence that AD pathology is affected by the combination of several factors, such as genetic and environmental factors . Changes in gene expression have an impact on the progression of the pathology. Thus, it is necessary to
investigate the role of gene expression at early stages in the pathology in order to diagnose and begin treatment earlier. Several of the new drugs are firstly tested in AD mouse models. It is therefore of great importance to define in detail transcriptional profile changes in these models. Here, I provided new insights into changes in gene expression at different contexts of cognitive
deficits.
First, I assessed the behavioral phenotype, transcriptional state and alternative exon usage related to early AD stages in APPPS1-21 mice, a well-established model of AD-like pathology. The present results indicate that APPPS1-21 transgenic males and females develop an undistinguishable rapid progression of AD, showing cognitive impairments restricted to spatial
memory at 3 months of age. Cognitive deficits declined with age, and mice performed worse in spatial learning and memory test at 9 months of age, compared to their 3-month old counterparts. Moreover, APPPS1-21 hippocampal subregions (CA1 and DG) showed gender and subregion-specific changes in gene expression and alternative exon usage already at 3 months of age. Despite the fact that APPPS1-21 hippocampal subregions and genders showed transcriptomic differences at the individual level, similar global biological processes were affected in these hippocampal subregions. The findings of this study reveal that two global processes occur in the APPPS1-21 hippocampal subregions at 3 months of age. First, there is an activation of genes involved in compensatory mechanisms, presumably as an attempt to return to a non-pathological status (increased of synaptic activity and neurogenesis). Second, and due to the fast progression of the disease in this model, there is a deregulation of pathways typically altered in late AD stages, such as energy metabolism and protein synthesis. Restoring the mitochondrial and ribosomal functions might be a promising therapeutic strategy to treat the AD-related memory decline.
In this study I also identified for the first time a gender-specific transmission to F1 offspring of epigenetic factors induced by the paternal origin in the APPPS1-21 mouse model, promoting cognitive and genetic changes to F1. There is increasing evidence that epigenetic information complements the genetic inheritance from parents to the offspring. The described findings uniquely revealed that wild-type offspring of APPPS1-21 transgenic fathers, but not mothers, showed spatial cognitive impairments, transcriptomic changes and alternative exon usage at 3 and 9 months of age (only behavior). These changes were associated with specific expression of small RNAs in the sperm. It is
interesting to note that the majority of small RNAs expressed in APPPS1-21 transgenic fathers were small nuclear RNAs (snoRNAs) and Piwi-interacting RNAs (piRNAs). Hence, it is the first time to my knowledge that snoRNAs and piRNAs are described as potential transmitters of intergenerational inheritance. These data provide evidence for the existence of new factors that contribute to the phenotype of wild-type and transgenic mice born to APPPS1-21 transgenic
parents. This novel information is crucial to take into account when analyzing the behavioral phenotype and for future colony breeding strategies of this mouse model and potentially also other transgenic lines. It will be essential in the future to complement the genetic information with epigenetic information in animal breeding.
Finally, I identified genes and pathways altered exclusively in aged mice that showed cognitive deficits but not in aged mice with intact cognitive abilities. Aging is the major risk for developing Alzheimer’s disease (AD). Thus, it is logical to think that aged mice with cognitive deficits will share more molecular alterations with AD mice than aged-mice with intact cognitive abilities. I demonstrated that old mice (17 months of age) showed higher inter-individual variability in performance than young animals. From these individuals, I preselect aged mice with and without cognitive deficits. Interestingly, hippocampal brain subregions of cognitive impaired aged-mice showed deregulation of biological processes previously defined as hallmarks of
aging, such as energy metabolism, protein synthesis and RNA metabolism. The present data indicate that deregulation of these pathways affects specifically aged mice with cognitive deficits. Moreover, I identified specific small RNAs expressed in the blood that correlate with age cognitive variability. These findings suggest that they can be used as biomarkers for the evaluation of cognitive abilities.
In this thesis, I described several molecular pathways related to cognitive decline and potential candidates for future treatments of cognitive deficits associated with aging or Alzheimer’s disease. Moreover, I detected potential biomarkers in the blood to evaluate the cognitive abilities in mice in a non-invasive manner.
Furthermore, I identified for the first time novel forms of small RNAs that are associated with the transmission of behavioral and molecular changes in wild-type offspring induced by the transgenic parental genotype in a gender-specific manner. This present study raises new issues to consider when mating transgenic mice, defining an appropriate control group and interpreting behavioral results. | de |