Distinct transcriptomic responses to Aβ plaques, neurofibrillary tangles, and APOE in Alzheimer's disease

• Published in: Alzheimer's & dementia 2024-01, Vol.20 (1), p.74-90
• Main Authors: Das, Sudeshna, Li, Zhaozhi, Wachter, Astrid, Alla, Srinija, Noori, Ayush, Abdourahman, Aicha, Tamm, Joseph A., Woodbury, Maya E., Talanian, Robert V., Biber, Knut, Karran, Eric H., Hyman, Bradley T., Serrano‐Pozo, Alberto
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; amyloid‐β plaques; APOE; Apolipoprotein E4 - genetics; Brain - metabolism; Brain research; Consortia; Cortex; Disease; Donors; Ethanol; Gene expression; Gene Expression Profiling; Genes; Genomes; Genotype & phenotype; Humans; laser capture microdissection; Lasers; Metabolism; Neurodegeneration; Neurofibrillary Tangles; Neuroinflammatory Diseases; Neuropathology; Plaque, Amyloid - metabolism; Quality control; RNA‐sequencing; Transcriptome
• ISSN: 1552-5260; 1552-5279; 1552-5279
• DOI: 10.1002/alz.13387

INTRODUCTION Omics studies have revealed that various brain cell types undergo profound molecular changes in Alzheimer's disease (AD) but the spatial relationships with plaques and tangles and APOE‐linked differences remain unclear. METHODS We performed laser capture microdissection of amyloid beta (Aβ) plaques, the 50 μm halo around them, tangles with the 50 μm halo around them, and areas distant (> 50 μm) from plaques and tangles in the temporal cortex of AD and control donors, followed by RNA‐sequencing. RESULTS Aβ plaques exhibited upregulated microglial (neuroinflammation/phagocytosis) and downregulated neuronal (neurotransmission/energy metabolism) genes, whereas tangles had mostly downregulated neuronal genes. Aβ plaques had more differentially expressed genes than tangles. We identified a gradient Aβ plaque > peri‐plaque > tangle > distant for these changes. AD APOE ε4 homozygotes had greater changes than APOE ε3 across locations, especially within Aβ plaques. DISCUSSION Transcriptomic changes in AD consist primarily of neuroinflammation and neuronal dysfunction, are spatially associated mainly with Aβ plaques, and are exacerbated by the APOE ε4 allele.