Uncovering new tau aggregation and spreading mechanism through AD tau‐seed interactome analysis

Abstract

AbstractBackgroundPathological tau aggregates are key features of Alzheimer’s disease and other tauopathies. The current research aims to understand how tau aggregates spread in AD patient brains, but the mechanisms remain unclear. Our recent‐published study found that the protein Bassoon plays a key role in tau spreading and pathology in a mouse model for tauopathy using mass spectrometry to identify proteins interacting with tau seeds. Considering our finding enhancing the relevance of tau‐seed interactor on disease pathology, we aim to characterize the interactome of the tau‐seed isolated from AD brains using a similar approach.MethodIn this study, we used Size Exclusion Chromatography (SEC) to separate TBS‐soluble AD and healthy brain extracts into fractions and measured tau seeding activity using a flow cytometry‐based biosensor cell line (n = 3). Then, the fractions with higher seeding activity were subjected to immunoprecipitation to isolate the tau seed and performed a TMT‐tags‐based unbiased quantitative mass spectrometry to uncover the specific tau species involved in tau propagation and identify new tau‐seed interactors.ResultThe strongest seeding activity in AD brains was found in fraction 9, which contains high molecular weight (HMW) proteins (>2,000 kDa), including only 5% of total tau, as assayed by ELISA for tau. Levels of tau were similar in fraction 9 in age‐matched controls but lacked seeding activity. Our bioinformatic analysis revealed that a total of 504 proteins interact with HWM tau without seeding activity isolated from controls and 1192 proteins interact with HWM tau‐seed isolated from AD cases. In addition, a total of 385 interacting proteins were found in both HWM tau from control and tau‐seed from AD cases. Interestingly, DAVID analysis as well as networks and interactions analysis (STRING analysis), revealed enrichment in proteins related to both synaptic and mitochondrial pathways.ConclusionOur findings significantly contribute to our understanding of the mechanisms involved in tau propagation and offer new insights into the potential for targeting tau‐seed interactions as a therapeutic strategy for tauopathies. Previously, we have identified BSN as a key interactor of tau seeds, and our data suggest that inhibiting these interactions could represent a promising new approach to treating these debilitating conditions.