# Transcriptional Profiling of Hippocampus Identifies Network Alterations in Alzheimer's Disease
## 4 Discussion  
Computational analyses based on high-throughput technologies such as microarray and Next-Generation Sequencing (NGS) have grown rapidly in recent years. Nevertheless, few analyses have been performed on AD, and those often involved a single dataset and only a few samples [30]. Our study used six open public GEO datasets containing gene expression levels of AD samples from hippocampus and normal samples and a hypothesis-based research design. We performed a differential expression analysis for each dataset comparing gene expression data on AD vs. healthy samples. Then, we generated a list of consensus DEGs found in at least two GEO datasets, obtaining 76 DEGs (40 down-regulated genes and 36 up-regulated genes). We verified whether the 76 DEGs are targets of known drugs in at least two of three drug databases (DGIdb, DrugCentral, and The Drug Repurposing Hub). Overall, we found that 9 out of the 40 down-regulated genes interact with 34 known drugs and 3 out of the 36 up-regulated genes interact with 9 drugs. In particular, we found that the down-regulated gene MET is the gene with the highest number of interacting drugs. Among the drugs, we found Crizotinib, Gefitinib, and Pazopanib. Crizotinib, an anticancer drug inhibitor of the receptor tyrosine kinase, acts on the down-regulated MET gene. It has been observed to be a potent inhibitor of SHIP2 [31]. Inosito 5\({}^{\prime}\)-phosphatase 2 containing the SH2 domain of SHIP2 is a lipid phosphatase that produces fosfatidilinositolo-3,4-bisfosfato from fosfatidilinositolo-3,4,5-trisofato and is involved in many neurodegenerative diseases [31]. A recent study showed that SHIP2 inhibition decreased \(\beta\)-amyloid-induced tau hyperphosphorylation and reduced memory impairment in a transgenic mouse model of AD [32]. This indicates that SHIP2 may be a promising target for AD. Gefitinib, an epidermal growth factor receptor (EGFR) inhibitor approved for the treatment of cancer, also acts on the MET gene. It was recently identified as a potential lead compound for \(\beta\)-secretasi (BACE-1), a potential target for the treatment of AD [33]. Another drug that acts on the MET gene is Pazopanib, whose role has been examined in mouse models that express mutant human tau P301L (TauP301L) or the precursor protein of triple mutant amyloid (3x-A\(\beta\)PP) [34]. Pazopanib can cross the blood-brain barrier without detectable peripheral side effects and reduces the expression of p-tau in TauP301L mice [26]. Pazopanib achieves a brain concentration sufficient for the inhibition of various tyrosine kinases, including vascular endothelial growth factor receptors (VEGFRs) [34]. Furthermore, pazopanib does not alter \(\beta\)-amyloid or astrocyte levels in 3x-A\(\beta\)PP mice, but modulates some inflammatory markers (IP-10, MIP-1\(\alpha\), MIP1\(\beta\), and RANTES) [34]. All this suggests that Pazopanib may be involved in the clearance of p-tau and in the modulation of astrocytic activity in taopathies. Interestingly, for up-regulated genes, we found COMT as a gene with more interacting drugs. Among the drugs, we found toclapone and entacapone. Tolacapone and entacapone act on the up-regulated gene COMT. They are used with levodopa for the symptomatic treatment of [PERSON]'s disease. In a previous study, toclapone and entacapone were studied for their potential ability to inhibit hexapeptide derived from tau [35]. It was found that toclapone and entacapone show antiplatelet properties against \(\beta\)-amyloid and \(\alpha\)-synuclein. Tolacapone showed a better inhibition of aggregation of the tau-derived hexapeptide and could be used for the treatment of AD due to its greater penetration into the central nervous system compared with entacapone [35]. Then, we built a network of co-expressed genes using WGCNA on an independent GEO dataset. The network was constructed considering gene expression levels of 76 DEGs. We obtained a module of 64 genes with ACOT7, ATP8A2, CDC42, GAD1, GOT1, INA, NCALD, and WWTR1 as the genes with a higher degree centrality.