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

Abstract

INTRODUCTIONOmics 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.METHODSWe 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.RESULTSAβ 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.DISCUSSIONTranscriptomic 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.

Landscape of brain myeloid cell transcriptome along the spatiotemporal progression of Alzheimer’s disease reveals distinct sequential responses to Aβ and tau

“…Significant correlation indicated by *** p value < 0.001, ** p value < 0.01, * p value < 0.05, grey boxes indicate insufficient data (number of overlapping genes between data sets < 10). AD1 and AD2 human microglia signatures from [ 16 ]; laser capture microdissected samples from [ 9 ] with signatures “Das_LCM_Plaque” (ThioflavinS + plaques), “Das_LCM_Peri_Plaque” (50 µm area around plaques), “Das_LCM_NFT” (neurofibrillary tangles with the 50µm area around them), “Das_LCM_Distant” (area > 50µm away from plaques), “Das_LCM_Plaque_vs_NFT” (ThioflavinS + plaques vs. neurofibrillary tangles); human iPSC-derived microglia-like cells transplanted into mice, with signatures CRM2 cytokine response 2, CYT/CRM1 cytokine response 1, DAM (disease associated), HLA antigen-presenting response, HM homeostatic, IRM (Interferon response), RM (ribosomal response), TRANS transitioning CRM from [ 32 ]; and primary mouse microglia tau fibril response genes from [ 51 ] …”

“…3 d, Gerrits et al “AD1” p values < 0.01 and < 2e-5, respectively, and “Wang_Tau_Fibril” p values < 2.8e-6 and < 0.05, respectively). Furthermore, the Aβ-associated cross-region clusters 5 and 8 showed the strongest correlation with “AD1” signatures (rho = 0.8 and 0.7, respectively; p values < 2.22e-16 for both), positive correlations with laser capture microdissected plaques and peri-plaque signatures (“Das_LCM_Plaque”: rho = 0.61 and 0.55, with p < 8.3e-6 and < 1.9e-6, respectively, and “Das_LCM_Peri_Plaque”: rho = 0.54 and 0.56, with p < 0.05 and < 0.01, respectively) [ 9 ], and a negative correlation with “Mancuso_HM” (homeostatic microglia, rho = – 0.48 and – 0.49, with both p values < 0.05), and cluster 5 additionally showed a positive correlation with “Mancuso_DAM” ( p < 0.05) (Fig. 3 d).…”

“…3 d, Fig. S3a), with genelists from public data included i) AD1 and AD2 signatures from [ 16 ], ii) laser capture microdissected samples from [ 9 ], with the following signatures:”Das_LCM_Plaque” (ThioflavinS + plaques), “Das_LCM_Peri_Plaque” (50µm area around plaques), “Das_LCM_NFT” (neurofibrillary tangles with the 50 µm area around them), “Das_LCM_Distant” (area > 50 µm away from plaques), “Das_LCM_Plaque_vs._NFT” (ThioflavinS + plaques vs. neurofibrillary tangles), iii) CRM2 (cytokine response 2), CYT/CRM1 (cytokine response 1), DAM (disease-associated), HLA (antigen-presenting response), HM (homeostatic), IRM (Interferon response), RM (ribosomal response), TRANS (transitioning CRM) signatures from [ 32 ], and iv) tau fibril response genes from [ 51 ]. For comparison with mouse genelists, mouse gene symbols were converted to human gene symbols with biomaRt (v2.50.3, [ 13 ]).…”

SARS-CoV-2-Induced Type I Interferon Signaling Dysregulation in Olfactory Networks Implications for Alzheimer’s Disease

“…In our original hypothesis, the IFN-I response against endogenous DAMPs such as Aβ would be enhanced by an exogenous IFN-I signal [3]. In order to determine the overlap between these signatures and those previously reported in Alzheimer's disease transcriptomes, we specifically selected the study of Das and colleagues [34] as it provides spatially resolved transcriptomic data on IFN-I responses elicited by Aβ plaques. Shared genes between IFN-I responses in the nasal epithelium (ciliated cells), OB, Amygdala, and the IFN-I response versus amyloid plaques would then be scrutinized via Agora in order to determine whether they are associated with an increased susceptibility to AD.…”

“…For the Alzheimer's disease datasets, we selected data from Das and colleagues [34] as it reported on sequencing of spatially resolved data, accounting for gene expression changes in relation to either Aβ plaques or neurofibrillary tangles. This unique dataset would allow us to detect, if present, IFN-I signatures in glia and in association with either pathology [36] and, by comparing them with the COVID-19 IFN-I signatures, determine overlap.…”