Interregional Gene Expression Analysis Identifies Signature of Cerebellar Resistance to AD Tauopathy

Abstract

AbstractBackgroundThe appearance of neurofibrillary tangles (NFTs) reflects both their spatial location within affected connectivity networks and the intrinsic vulnerability of neuronal populations to their formation. Here we disaggregate human gene expression data on the basis of connectivity to identify differentially expressed genes (DEGs) associated with neuroprotection against tauopathy.MethodTranscriptomic analysis focused on prefrontal cortex (PFC) and cerebellum, which both associate with the default mode and other AD‐affected networks. However, whereas PFC is vulnerable to tauopathic neurodegeneration, the cerebellum atrophies without NFT formation or cell loss. To identify candidate mediators of selective vulnerability, gene expression patterns in both regions from AD and control brains were calculated and then subjected to cell‐type specific enrichment analysis (CSEA), gene set enrichment analysis (GSEA), and transcription factor interaction network (TFIN) analysis. To validate candidate effector genes, prioritized chaperones were incubated with tau protein to test for suppression of biochemically induced fibrillization. The resulting distribution of soluble and aggregated tau was measured by sedimentation.ResultsCSEA revealed DEGs that changed in parallel between regions originated primarily in glia and microglia. GSEA identified these as belonging to Gene Ontology (GO) categories associated with host response and ion homeostasis. Of 446 genes, 379 were linked in a TFIN, with the most central nodes including transcriptional regulators HBP1, EGR1, SERTAD1, and PER1. In contrast, DEGs changing in opposition were primarily neuronal. GSEA identified 14 heat shock genes, including nine chaperone proteins reported to regulate protein folding. Of 402 candidate vulnerability genes, 319 were linked in a TFIN, in which the most central hubs were long noncoding RNA NEAT1, and transcription factors BHLHE40, ZC3H10, and CREB3L4. Finally, aggregation and sedimentation of tau showed all nine chaperones antagonized biochemical fibrillization of 2N4R tau with octadecyl sulfate at substoichiometric ratios of chaperone to tau.ConclusionsOur study takes advantage of a selective vulnerability informed approach to gene expression and highlights the role of proteostasis and neuronal genes in protecting the cerebellum from tau lesions. This approach successfully identified biologically active effector genes and can be applied broadly to other neurodegenerative diseases featuring prion‐like pathology and will orient the field toward endogenous strategies of neuroprotection.