Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Biochemistry & Molecular Biology, Cell Biology, GENE-EXPRESSION, A-BETA, COGNITIVE DECLINE, GENOMIC ANALYSIS, HUMAN BRAIN, CELL-TYPES, COMPLEMENT, MICROGLIA, TISSUE, PATHWAY, Alzheimer’s disease, amyloid plaque, astrocyte, cellular phase, complement cascade, in situ sequencing, microglia, myelination, oligodendrocyte, spatial transcriptomics, Alzheimer Disease, Amyloid, Amyloid beta-Peptides, Animals, Brain, Complement System Proteins, Disease Models, Animal, Gene Expression Profiling, Humans, Lysosomes, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Myelin Sheath, Oxidative Stress, Sequence Analysis, DNA, Transcriptome, G0B9219N#54969401, G0C0919N#54970009, 06 Biological Sciences, 11 Medical and Health Sciences, Developmental Biology, 31 Biological sciences, 32 Biomedical and clinical sciences

Abstract:

Although complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer's disease (AD), little is known about the molecular changes and cellular interactions that characterize this response. We investigate here, in an AD mouse model, the transcriptional changes occurring in tissue domains in a 100-μm diameter around amyloid plaques using spatial transcriptomics. We demonstrate early alterations in a gene co-expression network enriched for myelin and oligodendrocyte genes (OLIGs), whereas a multicellular gene co-expression network of plaque-induced genes (PIGs) involving the complement system, oxidative stress, lysosomes, and inflammation is prominent in the later phase of the disease. We confirm the majority of the observed alterations at the cellular level using in situ sequencing on mouse and human brain sections. Genome-wide spatial transcriptomics analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.