GSE168429
Identification and drug-induced reversion of molecular signatures of Alzheimer´s disease onset and progression in AppNL-G-F, AppNL-F and 3xTg-AD mouse models (RNA-seq: WT/NLGF)
Alzheimer's disease (AD) is the most common form of dementia. Over fifty years of intense research have revealed many key elements of the biology of this neurodegenerative disorder. However, our understanding of the molecular bases of the disease is still incomplete, and the available medical treatments for AD are mainly symptomatic and hardly effective. Indeed, the robustness of biological systems have revealed that the modulation of a single target is unlikely to yield the desired outcome, and we should move from gene-centric to   systemic therapeutic strategies. Here, we present the complete characterization of three murine models of AD at different stages of the disease (i.e. onset, progression and advanced). To identify genotype-to-phenotype relationships, we combine the cognitive assessment of these mice with histological analyses and a full transcriptional and protein quantification profiling from hippocampus. Comparison between the gene and protein expression trends observed in AD progression and physiological ageing exposed certain commonalities, such as the upregulation of microglial and inflammation markers. However, although there is an accelerated ageing in AD models, there are other factors specifically associated with A_ pathology. Despite the clear correlation between mRNA and protein levels of the dysregulated genes, we discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable. Indeed, we show that at least two of these proteins, namely lfit3 and Syt11, co-localize with A_ plaques in the brain. Finally, we derive specific A_-related molecular AD signatures, and we look for drugs able to globally revert them. We found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice   while reducing A_ plaques in the hippocampus and partially restoring the physiological levels of AD signature   genes to wild-type levels. Overall design: We analyzed the gene expression changes in the hippocampus of 6 months old AppNL-G-F mice treated with Etodolac (50 mg/kg), dexketoprofen (15 mg/kg), fenoprofen (50 mg/kg) and bendroflumethiazide (20 mg/kg) and the corresponding controls (vehicle-treated AppNL-G-F and Appwt/wt mice). We analyzed four mice per condition.