Proteomic similarities in Alzheimer’s disease and epilepsy brains highlight the important role of tau
Year: 2020
Type: article
Abstract: Background Alzheimer's Disease (AD) patients are more likely to experience epileptic seizures, and cognitive impairment is a frequent comorbidity in patients with epilepsy. Emerging findings indicate a common link between epilepsy and AD, however our understanding of the pathological changes shared between these two diseases is limited. Therefore, our aim was to determine whether there are common protein changes associated with both epilepsy and AD using an unbiased proteomics approach. Method We used label‐free mass‐spectrometry to quantify protein differences in the human epileptic hippocampus (epilepsy vs controls; n=14/group) and compared these results to differentially expressed proteins in AD generated by a meta‐analysis of the 10 most comprehensive AD proteomics studies. Result 777 proteins were significantly altered in the hippocampus in epilepsy. A significant proportion of these protein changes were also observed in AD (263/777 similar protein changes; p<0.0001). Proteins altered in both epilepsy and AD were predominantly excitatory neuron specific proteins (enrichment p<0.0001). Network analysis showed that proteins altered in both epilepsy and AD were most significantly involved in remodelling of epithelial adherens junctions (17/57 proteins, p=2.37x10‐16), clathrin‐mediated endocytosis signalling (21/160 proteins, p=2.98x10‐12) and phagosome maturation (17/114 proteins, p=4.81x10‐11), suggesting that the endosomal/lysosomal system dysfunction is a key factor for both epilepsy and AD pathogenesis. Shared protein alterations also indicated a decrease in synaptic proteins (enrichment p=6.52x10‐21), confirming that synapse loss or dysfunction is a common feature of both diseases. Interestingly, tau was identified as the most significant upstream regulator of proteins altered in both epilepsy and AD (p=4.53x10‐36). Furthermore, there was a significant overlap between proteins altered in both epilepsy and AD and proteins present in our recently generated phosphorylated tau interactome (32/125 pTau interactome proteins, p<0.0001). Together, this suggests that tau may have an important pathological role in both epilepsy and AD. Conclusion AD and epilepsy have many common protein changes in the brain. Tau may have an important role in mediating many of these common protein changes in AD and epilepsy.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.046234
Institutions: New York University, The University of Sydney
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W3111873761