Developing Topics

Background: Alzheimer's disease (AD) and primary age-related tauopathy (PART) both hyperphosphorylated-tau (pTau)-positive neurofibrillary tangles (NFTs) but differ in the spatial pTau development and Aβ-positive in the hippocampus. Cognitive status has been shown to be related to the overall hippocampal pTau burden, as well as the presence of β-amyloid deposit. Spatially dissecting the subregions and the cell-type-specific molecular dynamics within the hippocampus among control, PART, and AD individuals is crucial for understanding the mechanisms underlying AD progression. This study aims to construct the transcriptome-wide, high-resolution atlas of human hippocampus across control, PART, and AD subjects to delineate the cellular and molecular dynamics linked to the progression of AD.

Methods: Human hippocampus samples were primary collected from six Asian subjects (two AD, three PART, and one control; aged 79-92) for our 10X Visium spatial transcriptome and single-nucleus RNA-seq studies, as well as subsequent analysis. After identifying the subregions of hippocampus by clustering algorithms and manual annotation, differential gene expression (DGE) analysis was conducted to uncover the region-specific molecular alternations across controls, PART, and ADs. Deconvolution using Bayesian methods provided a detailed assessment of cellular composition and transcriptional signatures. Cell-Chat software was utilized to illustrate the regional specific inter-cellular interactions.

Results: Comparative analysis unveiled significant DEGs influencing specific hippocampal regions in control, PART, and AD samples, elucidating variations in cellular transcriptional expression levels across subject groups. Additionally, cell type-specific gene communication pathways and directions are delineated, including the associated protein expressions and functional pathways.

Conclusions: Our study of the human hippocampus reveals unique, cell-type-specific molecular alterations to PART and AD, compared to the control samples, illuminating potential mechanisms that drive the progression of AD.