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• W4380883668 abstract "Abstract Background Microglia, astrocytes, and neurons undergo profound functional alterations in response to amyloid‐β (Aβ) plaques and neurofibrillary tangles (NFTs) in Alzheimer’s disease (AD). Recent studies using human induced pluripotent stem cell‐derived glial cells and neurons, APOE knock‐in mice, and human brain bulk RNA‐seq have implicated the APOE genotype in these changes, but lack spatial information with respect to Aβ plaques and NFTs. Here we tested the hypotheses that (1) transcriptomic differences between AD and control subjects are maximum within and near Aβ plaques and NFT‐bearing neurons; (2) Aβ plaques and NFTs are associated with distinct transcriptomic changes; and (3) the APOE genotype differentially impacts the transcriptomic changes associated with Aβ plaques and NFTs in the AD brain. Method Laser capture microdissection (LCM) in cryostat sections was performed from superior temporal gyrus (BA22) cortex of human AD (n = 10, including n = 5 APOE ε4/ε4, n = 4 APOE ε3/ε3, and n = 1 APOE ε3/ε4) and age‐ and sex‐matched controls (n = 8). Thioflavin‐S‐positive Aβ plaques, the 50 µm halo around them, NFTs with the 50 µm halo around them, and areas far (>50 µm) from plaques and NFTs were laser‐capture microdissected and subjected to RNA‐sequencing to identify differentially expressed genes (DEGs). Result Aβ plaques had a greater impact on the transcriptome than NFTs (i.e., higher number of DEGs, both upregulated [logFC>0, unadj. P ‐value<0.05: 2,623 vs. 1,230 genes; adj. P ‐value<0.05: 1,152 vs. 0 genes] and downregulated [logFC>0, unadj. P ‐value<0.05: 2,563 vs. 1,056 genes; adj. P ‐value<0.05: 827 vs. 0 genes]) relative to control cortex. Aβ plaques were characterized by upregulated microglial and downregulated neuronal genes, whereas NFTs had primarily downregulated neuronal genes. A gradient of Aβ plaques > plaque halo > NFTs > far areas was evident, with upregulation of neuroinflammation and downregulation of synaptic neurotransmission and energy metabolism‐related gene sets. Comparing APOE ε4 and APOE ε3 age‐ and sex‐matched homozygotes revealed greater changes in APOE ε4 homozygotes across locations. Conclusion Aβ plaques and, to a lesser extent, NFTs, concentrate the bulk of transcriptomic changes in the AD cortex. The APOE ε4 allele is associated with greater microglial and neuronal transcriptomic responses to Aβ plaques and NFTs, compared to APOE ε3 carriers. These findings will inform future spatial transcriptomics studies." @default.
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• W4380883668 date "2023-06-01" @default.
• W4380883668 modified "2023-10-12" @default.
• W4380883668 title "The <i>APOE</i>ε4 allele exacerbates the transcriptomic responses to Aβ plaques and neurofibrillary tangles in Alzheimer’s disease" @default.
• W4380883668 doi "https://doi.org/10.1002/alz.062783" @default.
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