Code and associated data directory for manuscript: Spatially Resolved Microglial Expression Around Aβ Plaques in Human Alzheimer's Disease Tissue

Code and accompanying data directory for the manuscript below. Data have been pre-processed through the following steps: FASTQ → DCC → probe-level quality control. The raw FASTQ and DCC files are available from NCBI GEO.

Title

Spatially Resolved Microglial Expression Around Aβ Plaques in Human Alzheimer’s Disease Tissue

Authors

Jack I. Wood^1,2, Georgia Ppasia^1,3#, Paul Rolland-Du-Roscoat^1,4#, Sneha Desai^1,2, Shamim Choudhury¹, Aya Balbaa¹, Daria Gavriouchkina⁵, Modesta Blunskyte⁵, John Hardy^5,6, Damian M. Cummings¹, Dervis Salih⁵, Jörg Hanrieder^2,6, Frances A. Edwards^1*

Affiliations

1 Department of Neuroscience, Physiology & Pharmacology, University College London, Gower Street, London WC1E 6BT, U

2 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at the University of Gothenburg, Mölndal Hospital, House V3, 43180 Mölndal, Sweden

3 Sainsbury Wellcome Centre, UCL, London, W1T 4JG, UK

4 Ecole Normale Supérieure Paris-Saclay, 91190 Gif-sur-Yvette, France

5 UK Dementia Research Institute, University College London, Gower Street, London WC1E 6BT, UK

6 Department of Neurodegenerative Disease, University College London Queen Square Institute of Neurology, Queen Square, London WC1N 3BG, UK

Experimental summary

NanoString GeoMx Digital Spatial Profiler (DSP) was applied to FFPE human hippocampus to profile microglia-enriched gene expression from donors with Alzheimer’s disease (AD) and cognitively unimpaired, amyloid-positive (CU-AP) controls. For each tissue, gene expression was captured from microglia directly contacting amyloid plaques (“plaque-associated”), (ii) microglia in the peri-plaque region, and (iii) microglia distant from plaques.

Manuscript Abstract

Using microglia-enriched spatial transcriptomics on human Alzheimer’s disease tissue, we identify distinct gene expression changes across microglia located in direct contact with plaques, in periplaque regions, and in areas distant from plaques. We define a group of plaque contact–only microglial (PCOM) genes whose expression increases exclusively in microglia directly contacting plaques. These genes show significant overlap with previously reported gene sets, suggesting that plaque-contacting microglia correspond to the well-characterised disease-associated microglia (DAM) and other AD-related gene-expression signatures. We further identify distinct co-expression networks associated with disease-relevant covariates, including an immune module linked to APOE genotype and a synaptic–mitochondrial module negatively associated with Braak stage. Finally, we compare the human dataset to our previously published data from 18-month-old App^NL-F mice, generated using the same experimental paradigm and demonstrate cross-species concordance in gene expression within plaque-contacting microglia.