Title: Cellular atlas of Alzheimer’s disease
Funder: Medical Research Council

Abstract: The UK Dementia Research Institute (UK DRI) is an initiative funded by the Medical Research Council, Alzheimer's Society and Alzheimer's Research UK. Scientific abstract (around 400 words – max. 3,500 characters including spaces) The theme of the laboratory is to identify and characterize the cellular and molecular mechanisms which differentiate healthy brain ageing from dementia. In first instance, we are looking for the cellular alterations which, once initiated by the formation and deposition of protein aggregates (e.g. amyloid-beta and tau in Alzheimer’s disease), determine the clinical outcome of dementia. At the same time, our aim is to identify the cellular and molecular mechanisms that enable the preservation of intact brain functions in individuals which are clinically devoid of dementia while displaying signs of biochemical neuropathology. Indeed, cognitively intact elderly people may still display extensive amyloid-beta deposition. Neurodegenerative diseases are characterized by the appearance of biochemically defined toxic insults which lead to stereotypical clinical presentations. As it appears increasingly evident, our current therapeutic approaches targeting the biochemical units causing disease are ill-timed, as by the time we can detect clinical signs of dementia, the biochemical mechanisms have already ignited self-sustaining cellular mechanisms which support pathology. Therefore, it is paramount to identify the cellular mechanisms leading to clinic manifestations of dementia, and we should do this by focusing not just on a single cell type, but on the whole set of cells making up the human brain, and on their interactions. Our approach is to use single cell genomics techniques, which allow to break down tissue heterogeneity and to identify changes in transcriptomic, epigenomic and proteomic makeup of individual cells. Aggregation of data collected across thousands of cells for each single brain tissue sample allows then to recapitulate the tissue-wide genomic and proteomic organization, while maintaining vital information about rare cell populations (e.g. activated microglia, perivascular macrophages,…) which cannot be captured using a classical “bulk tissue” approach. We collaborate extensively with the Queen Square Brain Bank, to access neuropathologically well-characterized tissue samples coming from people for which extensive clinical records are available. We will compare the transcriptome and epigenome of tissue samples from dementia-affected patients and from cognitively intact subjects, either displaying signs of protein aggregation or free from them. Thus, we will identify the mechanisms underlying resistance to pathology, and the cellular events leading to Alzheimer’s disease. The next step will be to identify ways through which we can activate the resistance pathways in affected patients, to delay or cure dementia. Of importance, our approach will highlight not just the genes responsible, but the actual cellular populations to target, making the design of a therapy more targeted, and hence more effective.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: NEUROLOGICAL