# Transcriptional Profiling of Hippocampus Identifies Network Alterations in Alzheimer's Disease
## 4 Discussion
A previous study identified CDC42 as one of the genes associated with AD that, along with other genes, is able to predict AD and cardiovascular disease in blood samples [26]. The 64 genes are mainly enriched in the clathrin coat assembly, synaptic vesicle endocytosis, and DNA damage response signal transduction by p53 class mediator pathways. There is a correlation between clathrin coat assembly and A\(\beta\) protein. The extracellular deposition of A\(\beta\) protein is one of the most important neuropathological features of AD. APP is the gene that produces A\(\beta\) after it is internalized by clathrin-mediated endocytosis. Thus, an increase in extracellular amyloid deposition reflects an increase in the production of A\(\beta\)[36]. In addition, alterations in endocytosis can lead to the over-production of A\(\beta\) protein [37]. We further investigated the protein functional network that involves the 76 consensus DEGs. We found a network of 39 interacting proteins consisting of 81 interactions. Among them, MCODE identified AMPH, CA10, CALY, NEFL, SNAP25, SNAP91, SNCB, STMN2, SV2B, SYN2, SYT1, and SYT13 as a cluster of interconnected genes. AMPH, CA10, CALY, NEFL, SNAP25, SNAP91, SNCB, STMN2, SV2B, SYN2, and SYT1 are common genes between the WGCNA module and the 12 genes found with MCODE. AMPH encodes a protein modulator of endocytosis in synapses [38]. AMPH knockout mice showed a reduced turnover of synaptic vesicle and cognitive deficits [39]. In addition, a reduced expression of AMPH was reported in AD brain regions [40]. The protein encoded by CA10 is involved in brain development and the central nervous system [41]. Moreover, a bioinformatics study revealed 15 genes, including CA10, to be hub genes and able to predict the occurrence of AD [42]. CALY regulates different aspects of the endosomal and synaptic processes. It is needed for endocytosis, degradation, and synaptic plasticity. CALY could be an interesting drug target for neurological diseases such as AD and schizophrenia [43]. Previous studies revealed that elevated levels of NEEFL are a known indicator of early neuronal injury and axonal damage in preclinical AD [44]. SNAP25 is a well-established biomarker of functional synapses as it is a component of the SNARE complex that regulates synaptic communication via synaptic vesicles [45]. In a previous study, elevated levels of SNAP25 were present in cerebrospinal fluid (CSF) of AD patients, suggesting it as a biomarker for early diagnosis [46]. We also found another synaptosome-associated protein, SNAP91. SNAP91 regulates synaptic vesicle transport, and its dysregulation could damage synaptic transmission [47]. SNAP91 is involved in several neurodegenerative diseases, such Parkinson's disease and AD, where low levels of SNAP91 have been found [48; 49]. SNCB encodes a protein involved in neuronal plasticity. High levels of SNCB were observed in AD in CSF and plasma [50]. STMN2 belongs to the stathmin family and plays a role in microtubule dynamics. Microtubules are involved in axonal signaling transduction and neuronal growth [51]. However, there is not a clear association between STMN2 and AD. Previous studies found a decrease in SV2B and SYN2 in AD patients [52; 53]. SYT1 and SYT13 are components of a synaptotagmin family with a role in neurotransmitter release. High levels of SYT1 were found in CSF of AD patients. The down-regulated genes CA10 and CALY are targeted by known drugs. CA10 interacts with zonisamide, and CALY with apomorfina, dozapina, and trifluoreprazine. The up-regulated genes COMT, PRKG1, and PTAFR present in the WGCNA module are targets of known drugs. No known drug acts on genes present in the MCODE module. Several works suggested that the primary pathological hallmarks of AD are A\(\beta\) plaques and NFTs. Additional changes could occur in the brain of AD patients as secondary responses. However, we could not determine whether the alterations found in our study are directly linked to the primary or secondary AD changes.