– WesternND

In the last century, life expectancy in Europe has increased from 44 in 1900 to 80 years in 2020. However, people are living longer but experiencing more years in ill health, with an increase in age-related neurodegenerative diseases. Lifestyle changes have also contributed to a rise in obesity, which is a known risk factor for dementia, and has been linked to chronic inflammation and immune sensitization. To identify inflammatory factors driving chronic inflammatory diseases we have made use of an unbiased large-scale multi-omic in vivo screen evaluating 1100 parameters. Using machine learning techniques we have identified that the consumption of a Western diet (WD) in models of atherosclerosis triggers a specific lipid, Sphingomyelin d18:1/14:0 (S14). This new endogenous trigger of inflammation binds TLR4 and activates microglia, which have a central role in Alzheimer's disease (AD) and frontotemporal dementia (FTD). This proposal aims to determine whether S14 could be a key signaling factor linking WD, obesity and atherosclerosis with dementia. The proposal will examine the role of S14-driven neuroinflammation and neurodegeneration across human and murine studies using patient cohorts and animal models. Lipidomics will be performed on blood and cerebrospinal fluid (CSF) from patient cohorts with neurodegenerative disease (AD and FTD) and atherosclerosis. Mice with AD and FTD pathology will receive WD and TLR4 inhibition with TAK242 to prevent S14 signaling, and to inhibit downstream epigenetic changes. Microglia will be prepared for single cell RNA sequencing and ATAC sequencing to identify epigenetic and transcriptional changes, which will be functionally tested with RNA therapeutics. Additionally, CSF immune cells of aged atherosclerosis individuals will undergo sequencing. S14- and TAK242-treated iPSC-derived brain organoids from patients with AD and FTD will delineate the role of S14 signaling in driving neuroinflammatory changes in human cells. The project aims to uncover shared gene pathways and transcriptional networks underlying the WD/S14-induced changes, assess whether the networks are shared across human and murine microglia, and identify whether TLR4 and its epigenetic targets can be exploited therapeutically to mitigate the risk of neurodegenerative disease. The consortium includes multidisciplinary specialists in clinical research, animal studies, systems biology, epigenetics and bioinformatics. The research could highlight S14 as a sensitive biomarker for AD or FTD progression and provide new targets for personalized therapies in dementia.