The APOEε4 allele exacerbates the transcriptomic responses to Aβ plaques and neurofibrillary tangles in Alzheimer’s disease

Abstract

AbstractBackgroundMicroglia, 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.MethodLaser capture microdissection (LCM) in cryostat sections was performed from superior temporal gyrus (BA22) cortex of human AD (n = 10, including n = 5 APOEε4/ε4, n = 4 APOEε3/ε3, and n = 1 APOEε3/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).ResultAβ 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 APOEε4 and APOEε3 age‐ and sex‐matched homozygotes revealed greater changes in APOEε4 homozygotes across locations.ConclusionAβ plaques and, to a lesser extent, NFTs, concentrate the bulk of transcriptomic changes in the AD cortex. The APOEε4 allele is associated with greater microglial and neuronal transcriptomic responses to Aβ plaques and NFTs, compared to APOEε3 carriers. These findings will inform future spatial transcriptomics studies.