Molecular signatures and spatial distribution of disease-associated cellular populations in early-onset Alzheimer's disease mouse brain

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder. Grasping the pathological transformations in early-phase AD is important. Integrating single-cell and spatial transcriptomics with the pathophysiology of AD from the same origin permits to delineate molecular characteristics and spatial arrangement of cellular populations without individual differences, however, such experimental designs have been ignored in current studies. Here, we use a single-source experimental framework to create a multimodal dataset of disease-susceptible region in early-onset Alzheimer's Disease (EOAD) mouse. Predicated on amyloid-beta (Aß) immunopathology, a profile of disease-associated alterations is discerned. Mature myelinating oligodendrocytes within fiber tracts exhibit compromised fatty acid synthesis and energy-related processes. Region-specific glutamatergic neurons demonstrate impaired synaptic formation, coupled with transcriptomic modifications that encompass energy homeostasis, lipid metabolism and cellular adhesion. Disease-associated astrocytes, aggregating around Aß deposits, exhibit neuron-related changes in oxidative phosphorylation (OxPhos) and metal ion responses. This investigation serves as a resource for exploring disease signature across multimodal, which provides a basis for finding the progression mechanisms of AD. Overall design: The experimental design consists of three phases: mouse preparation, tissue processing and molecular detection. The mice are divided into two groups: the wild-type (WT) group (C57bl/6, n= 12, 6 months) and the 5×FAD group (5×FAD, n= 12, 6 months). All mice are euthanized and their brains are isolated for further analysis. A subset of WT group (n=3) and 5×FAD group (n=3) is selected and dissected into two hemispheres. Single-nucleus RNA sequencing (snRNA-seq) is performed on the right hemisphere. Owing to the well-known involvement of the hippocampus in AD, one left hemisphere from each group is chosen for coronal sectioning around the hippocampus. Three slices are obtained from each group, representing the large (L), middle (M) and small (S) regions of the hippocampus. These slices effectively capture changes in the anterior, middle and posterior areas of disease-prone region. Subsequently, the sections are subjected to immunofluorescence staining and spatial transcriptomics sequencing.