Differential spatial transcriptome profile of the hippocampal formation of protected PSEN1 E280A familial Alzheimer’s disease cases

Abstract

AbstractBackgroundWe have described two cases with ∼ 30 years of delayed disease onset among carriers of PSEN1 mutation E280A, suffering from familial Alzheimer’s disease (FAD). One case was homozygous for the ApoE Christchurch (hApoEch) mutation. This case showed sparse hyperphosphorylated tau (pTau) pathology in several cortical areas. The second case was heterozygous for the RELN‐COLBOS mutation and was globally affected by severe pTau and amyloid beta pathology, with evidence of localized cellular protection in the entorhinal cortex (EC). Here we used digital spatial profiling (DSP) transcriptomics to characterize the hippocampal formation of FAD protected cases and identify possible molecular mechanisms of protection.MethodsIn depth morphological characterization of the EC together with identification of thirteen different regions of interest (ROIs) were performed in Formalin‐fixed paraffinized 3 mm thick slides taken from the hippocampal formation (Fig. 1A) of the RELN‐COLBOS FAD case, the hApoEch FAD case, three FAD cases, and three sporadic Alzheimer’s cases (SAD). Slides were immunostained for NeuN and GFAP for morphological ROIs identification and processed for localized transcriptome analyses using the GeoMX DSP platform from Nanostring. Obtained data was processed for quality control, dimensionality reduction and differential gene expression (DGE) analyses.ResultsDimensionality reduction of transcriptomic data obtained from all ROIs and studied cases showed a distinctive distribution of ROIs belonging to both protected cases (Fig. 1B). Furthermore, DGE was observed in all sampled ROIs. ROIs such as hippocampal white matter or dentate gyri showed a higher number of differentially expressed genes due to a more homogeneous cellular composition of the ROIs (Fig. 1C). Also, EC and dentate gyrus from FAD protected cases showed distinctive molecular signatures compatible with excitatory neuronal pathways (Fig. 1D). Complementary morphological analyses showed increased neuronal density in the supragranular region of the EC in the RELN‐COLBOS FAD protected case, specifically in neuronal layer II.ConclusionOur results suggest that regardless of the protective gene conferring protection to FAD, the EC is one key protected structure with distinctive regional transcriptomic profiles suggesting the preservation of neuronal function in this region and hinting towards a possible therapeutic target in the protection against Alzheimer’s disease.