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One of the strongest risk factors for late onset AD is the loss-of-function (lof) variants in the °Õ¸é·¡²Ñ2 gene2. Understanding the impact of the TREM2 ±ô´Ç´Ú variants on gene expression in both disease and non-disease contexts will enable deeper understanding of its biology.    

Bulk and single nuclear transcriptomic methods have been used to generate datasets from retrospectively acquired brain tissue from AD and control donors and on a genetically stratified group of donors (TREM2 variant). This study has increased our quantitative and biological understanding of the role of TREM2 in AD. It has combined transcriptomic and lipidomic data with histological and genotyping data from AD and healthy control donors with and without the TREM2 variants. This work is in collaboration with Biogen and summarized in the preprint below.  

Brain perfusion and normal blood brain barrier integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and control brains to characterise pathological transcriptional signatures. We found that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. EC transcriptional signatures identified mechanisms for impaired β-amyloid clearance. Evidence for immune activation was found with upregulation of interferon signalling genes in EC and in pericytes (PC). Transcriptional signatures suggested dysregulation of vascular homeostasis and angiogenesis with upregulation of pro-angiogenic signals (HIF1A) and metabolism in EC, but downregulation of homeostatic growth factor pathways (VEGF, EGF, insulin) in EC and PC and of extracellular matrix genes in fibroblasts (FB). Our genomic dissection of vascular cell risk gene enrichment suggests a potentially causal role for EC and defines transcriptional signatures associated with microvascular dysfunction in AD. 

Using freshly resected brain tissue from McGill University’s ‘The Neuro’ state-of-the art biobanking platform, this project aims to systematically assess how differing processing techniques (time and temperature) cause artifacts in transcriptional data relevant to interpreting brain autopsy studies.  The collaboration between McGill and 911½ñÈÕºÚÁÏ UKDRI includes advanced bioinformatics and creates a user-friendly open science website where researchers can deposit their human brain transcriptional datasets and assess to what degree their data may be subject to processing artifacts associated with time and temperature. 

Brain perfusion and blood-brain barrier (BBB) integrity are reduced early in Alzheimer’s disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and non-diseased control brains to characterise pathological transcriptional signatures responsible for this. We show that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. Increased β-amyloid is associated with BBB impairment and a dysfunctional angiogenic response related to a failure of increased pro-angiogenic HIF1A to increased VEGFA signalling to EC. This is associated with vascular inflammatory activation, EC senescence and apoptosis. Our genomic dissection of vascular cell risk gene enrichment provides evidence for a role of EC pathology in AD and suggests that reducing vascular inflammatory activation and restoring effective angiogenesis could reduce vascular dysfunction contributing to the genesis or progression of early AD.