Spatial Transcriptomics for Investigating the Interaction between TDP-43 Proteinopathy and Hippocampal Sclerosis in Alzheimer's Disease

PROJECT SUMMARY Alzheimer's Disease (AD) stands as a formidable neurodegenerative affliction impacting millions globally. While substantial headway has been made in deciphering the genetic and molecular underpinnings of AD, critical questions persist regarding transcriptomic responses to hippocampal sclerosis (HS) and TAR DNA-binding protein of 43 kDa (TDP-43) proteinopathy, two established features of the disease. Aberrant gene expression has been linked to both HS and TDP-43 proteinopathy. Different TDP-43 species have been found to have distinct binding abilities to specific RNA regions and thus selectively influence its RNA-regulatory network. HS is accompanied by the disruption of the gene regulatory network involved in neuronal apoptosis. However, the transcriptomic impact of their interplay remains unexplored. Recently, we have characterized a unique phosphorylation-independent anti-TDP-43 monoclonal antibody specific for a new TDP-43 species in frontotemporal lobar degeneration (FTLD)-TDP type A and type B. The goal of this proposal is to investigate the regional and transcriptomic bases of the contribution of the new TDP-43 species and HS to AD. Our central hypothesis is that the interplay between TDP-43 proteinopathy and HS influences hippocampal transcriptomic abnormalities. In this study, we propose to combine the strengths of the unique anti-TDP-43 antibody and the state-of-the-art spatial sequencing developed to investigate the transcriptomic aspects of how novel TDP-43 species contribute to HS in AD. Aim 1 will quantitatively analyze the distributions of TDP-43 proteinopathy (new TDP-43 species) and neuronal loss in the hippocampi of AD brains. Aim 2 will determine hippocampal gene expression profiles associated with the new TDP-43 species using spatial sequencing technologies. The successful execution of this project will significantly advance our understanding of TDP-43 research, particularly in terms of our limited knowledge concerning pathologic TDP-43 species and its intricate association with HS in AD.