"We investigate key brain structures for memory formation and encoding, using a single cell genomics approach. My goal is to is understand the cellular and molecular basis of Alzheimer’s disease pathology. My ambition is to identify key cellular pathways that can be targeted for the prevention and treatment of dementia." Carlo Sala Frigerio
UK DRI Group Leader
Having trained at University College Dublin and held senior positions within VIB Leuven, Dr Carlo Sala Frigerio has come to UK DRI at UCL to build his own research group – bringing with him extensive knowledge of single cell technologies. Through this new programme he hopes to develop a cellular theory of dementia, tying together clinical and neuropathological knowledge of the disease with deep molecular characterisation of the brain.
1. At a glance
Deciphering dementia - one cell at a time
Alzheimer’s disease (AD) is characterised by the abnormal build-up of protein in the brain. Scientists believe that these protein aggregates and/or the mechanisms leading to their formation may be important in the progress of the disease. However, despite showing evidence of these pathology hallmarks in their brains, some people do not develop the clinical symptoms of the disease e.g. memory loss.
It is still unknown why some people may be protected from developing the symptoms of AD, but scientists believe the reason may lie in the reaction of surrounding cells to this abnormal protein. In a disease like AD, it is thought that immune cells, known as microglia, stop performing normal maintenance duties and become very reactive, causing damage to surrounding neurons. The difference between people that show clinical symptoms of AD and those that do not, may lie in the genetic make-up and the reaction of the microglia.
Dr Carlo Sala Frigerio’s group is following up on this line of enquiry by investigating how the complex biochemical changes and reactions taking place during AD affect different brain cell types. The team are utilising state-of-the-art technology to analyse individual cells as, even within the same cell type, small variations may be critical to our understanding of how the disease develops. The overall aim will be to identify key cellular changes during AD, which could then be targeted for therapeutic intervention.
2. Scientific goals
In the challenge to develop therapeutics for Alzheimer’s disease (AD) and other neurodegenerative conditions, a major need remains to understand how different types of brain cell react against initial pathological insults and during overt pathology, i.e. a cellular theory of dementia linking initial biochemical toxic stimuli with a recognisable clinical outcome.
Dr Carlo Sala Frigerio’s group studies the extensive heterogeneity of cells in the brain - the basis of the functional specification of different brain areas and neural circuits, underscoring the “selective vulnerability” phenomenon witnessed in neurodegenerative diseases. By using single cell genomics (SCG) technologies, the team can overcome the challenges of investigating cellular heterogeneity. SCG data are a revolutionary improvement over “bulk” nucleic acid analysis, which average the signal from all cells of a tissue sample. SCG technologies are able to translate an organ’s complexity into systematic lists of cell types and associated functions inferred from their transcriptional profiles, which can be used to generate high resolution cellular atlases.
After recently using this approach to identify an activated state in microglia in response to amyloid accumulation in mouse models of disease, Carlo and his team will utilise a single nucleus RNA-sequencing approach in post-mortem human brain tissue. He will investigate the cellular structure of brain areas selectively affected (e.g. hippocampal area CA1) and spared (e.g. presubiculum) by AD pathology, using the cells’ transcriptomes as proxy to infer their type, functions and state. Additionally, he will employ in situ hybridization/ sequencing methods, to map cell types and states in their spatial context in tissue.
The group will analyse post-mortem brain tissue donated by patients affected by AD and by cognitively intact subjects, to understand how cells are affected by disease and how cells are resilient to pathology in elderly subjects. Specific cellular mechanisms altered or induced by pathology will then be modelled in mouse models and in vitro human models (e.g. cerebral organoids), to identify their functional relevance and to pinpoint actionable targets for treatment.
Ultimately, Carlo hopes to understand how AD pathology develops in order to highlight potential therapeutic approaches, while also contributing to a deeper understanding of brain structure and function.
Main objectives and research goals:
1. Compile a data-driven taxonomy of cell types and states in the hippocampus during AD progression, by using the cellular transcriptome to infer cell identity and function.
2. Use spatially-resolved transcriptomics (ST) to characterise cell types and state in their tissue context.
3. Integrate transcriptomic datasets with neuropathological/clinical data to reconstruct the trajectory of cellular behaviours from the biochemical stress to clinical phenotype.
4. Develop and implement novel single cell methodologies to advance the research field.
3. Team members
Dr Melissa Salazar (Research Fellow)
Dr Rikesh Rajani (Postdoctoral Researcher) - shared with Dr Marc Aurel Busche
Within UK DRI:
- Prof John Hardy, UK DRI at UCL
- Prof Henrik Zetterberg, UK DRI at UCL
- Dr Dervis Salih, UK DRI at UCL
- Dr Marc Busche, UK DRI at UCL
- Prof Paul Whiting, UK DRI at UCL
- Prof Bart De Strooper, UK DRI at UCL
- Prof Paul Matthews, UK DRI at Imperial
- Dr Nathan Skene, UK DRI at Imperial
- Prof Caleb Webber, UK DRI at Cardiff
Beyond UK DRI:
- Prof Ken Harris, UCL
- Dr Mina Ryten, UCL
- Dr Tammaryn Lashley, Queen Square Brain Bank
Alzheimer’s disease, molecular neuropathology, single cell genomics, spatial transcriptomics, human brain
Single cell RNA and DNA sequencing, in situ sequencing, smFISH, bioinformatics
7. Key publications
Frigerio, C.S., Wolfs, L., Fattorelli, N., Thrupp, N., Voytyuk, I., Schmidt, I., Mancuso, R., Chen, W.T., Woodbury, M.E., Srivastava, G. and Möller, T., 2019. The Major Risk Factors for Alzheimer’s Disease: Age, Sex, and Genes Modulate the Microglia Response to Aβ Plaques. Cell reports, 27(4), pp.1293-1306.
Sala, C.F., Lau, P., Troakes, C., Deramecourt, V., Gele, P., Van, P.L., Voet, T. and De, B.S., 2015. On the identification of low allele frequency mosaic mutations in the brains of Alzheimer's disease patients. Alzheimer's & dementia: the journal of the Alzheimer's Association, 11(11), pp.1265-1276.
Sala Frigerio, C. and De Strooper, B., 2016. Alzheimer's disease mechanisms and emerging roads to novel therapeutics. Annual review of neuroscience, 39, pp.57-79.
Frigerio, C.S., Lau, P., Salta, E., Tournoy, J., Bossers, K., Vandenberghe, R., Wallin, A., Bjerke, M., Zetterberg, H., Blennow, K. and De Strooper, B., 2013. Reduced expression of hsa-miR-27a-3p in CSF of patients with Alzheimer disease. Neurology, 81(24), pp.2103-2106.
Mancuso, R., Van Den Daele, J., Fattorelli, N., Wolfs, L., Balusu, S., Burton, O., Sierksma, A., Fourne, Y., Poovathingal, S., Arranz-Mendiguren, A. and Frigerio, C.S., 2019. Stem cell derived human microglia transplanted in mouse brain to study genetic risk of Alzheimer's Disease. bioRxiv, p.562561.