Proteomics of the dentate gyrus reveals semantic-dementia-specific biology.

Abstract

Semantic dementia (SD) is a subtype of frontotemporal dementia (FTD) characterized by impaired word comprehension and semantic memory. The consistent neuropathological diagnosis is FTD-TDP subtype C, with TDP-43 protein aggregates in the temporal cortex and dentate gyrus of the hippocampus. Despite this striking clinicopathological concordance, the pathophysiological mechanisms remain largely unknown. We assessed the relative protein abundance changes in laser capture micro-dissected dentate gyrus of 15 SD patients and 14 age- and sex-matched non-demented controls using a label-free quantitative proteomics approach. We identified proteins and biological pathways that might be uniquely altered in SD, by comparing to 9 other large FTD and Alzheimer's Disease (AD) proteomics datasets of cortical brain tissue. Validation experiments on selected candidate proteins are ongoing, including immunoblotting. 145 of all 2414 detected proteins showed differential abundance (FDR<5%) in SD patients. 73 proteins were observed in at least 2 other proteomics studies in FTD/AD. The remaining 72 proteins (29 not observed, 43 in 1 out of 9 studies) were regarded as potentially SD specific and selected for further analyses. Functional enrichment revealed an overrepresentation of the cell-cell adherens junction and the cadherin-catenin complex, represented by multiple upregulated proteins within this complex, including CDH2/N-cadherin, CTNNB1/β-catenin, and JUP/plakoglobin. Our findings indicate an SD specific upregulation of cell adhesion proteins constituting the cadherin-catenin complex at the synaptic membrane. Validation of several proteins by immunoblotting is currently being performed. This study contributes to an improved understanding of the disease processes in SD, and demonstrates the value of quantitative proteomics to differentiate the pathophysiological mechanisms of specific subtypes of dementia.