"The primary focus of our lab is to study the cell biological basis of clearance mechanisms in neurons and microglia, and translate these findings to find an effective cure wherein amyloid load is lowered but with synapses stabilised." Lawrence Rajendran
UK DRI Group Leader
A renowned expert in cell biology of Alzheimer’s disease, Lawrence Rajendran was a Professor of Systems and Cell biology of Neurodegeneration at the University of Zurich before he moved to the UK as the van Geest Chair of Dementia Research at King's College London. He has won numerous awards including the European Young Scientist Grand Prize, German Neuroscience Society’s Schilling’s prize and the Breuer Award, as well as being listed in the 2009 World’s top 100 Scientists. In 2015 he founded ScienceMatters, publishing single science observations with a commitment to open science. He joins as Deputy Associate Director at UK DRI at King's, additionally leading a group researching amyloid formation and synapse loss in Alzheimer's disease.
1. At a glance
The impact of ageing on neurodegenerative diseases
Alzheimer’s disease is the most common form of dementia. There are many different risk factors that affect whether someone will develop the disease – but age is the biggest. The condition is caused by a gradual loss of connections between neurons in the brain, and much evidence points towards the build-up of abnormal proteins as a key causative factor. Eventually, this leads to the death of neurons together with the symptoms associated with the disease – including memory loss.
Prof Lawrence Rajendran is aiming to detangle the many different biological processes involved in ageing to identify common features that could be targeted to help prevent or treat age-related conditions including diseases that cause dementia. He is particularly focusing on unpicking the complex mechanisms at different stages of Alzheimer’s disease development – both during protein build-up and later on when there is a loss of connections between neurons, and cell death. Ultimately, Lawrence is hoping to identify and develop effective new drugs that can slow down or stop disease progression.
2. Scientific goals
Many neurodegenerative diseases have ageing as the main risk factor, suggesting that ageing-dependent mechanisms influence the disease process. Ageing is a complex process dictated by metabolic dysregulation at a systems level; not only does our anabolic metabolism “slow” down, but also ageing-specific pathways are upregulated, which involve mostly pathways that are of a catabolic nature. Thus, during ageing, there seems to be an imbalance that is skewed towards more catabolism where both the infrastructure, as well as the functionality of the system, start to disintegrate.
Prof Lawrence Rajendran's lab have recently shown that anabolic nutrient signalling, in neurons, inhibited lysosomal clearance and thus promoted amyloid accumulation. They also showed that, on the contrary, inhibition of this signalling pathway in neurons enhanced lysosomal clearance and reduced amyloid levels. However, when this pathway was manipulated in microglia, they not only displayed enhanced phagocytic activity and lysosomal amyloid clearance, but also “indiscriminately” pruned synapses. While on one hand, the enhanced phagocytic activity due to reduced nutrient signalling could clear the unwanted amyloid proteins, the fact that this also reduces synapses is of concern. In the late stages of ageing, insulin resistance could contribute to higher catabolic activity in both neurons and microglia that can create synaptic/neuronal atrophy, which further contributes to cognitive impairment.
Main objectives and research goals:
This programme will explore the central question: what components of the ageing process cause deficits in biological capacities and what roles do these have in neurodegeneration?
1. Cell biology of amyloid production in Alzheimer’s disease. Systems and cell biology approaches to investigate how amyloid beta is produced and forms amyloid.
2. Cell biology of amyloid clearance in neurons and microglia. Using systems biology approaches to investigate cellular mechanisms of amyloid beta regulation.
3. Biology of synapse loss in neurodegenerative diseases. Exploring the impact of the nutrient-sensing pathway and AD risk genes on the phagocytic activity of microglia, with a special focus on amyloid clearance and non-physiological synaptic pruning.
4. Therapeutic interventions. Developing drug compounds that can enhance the clearance of toxic amyloids while preserving synaptic structure and function.
3. Team members
Dr Mrityunjoy Mondal (Research Associate)
Shiden Solomon (PhD Student)
Ivo Carre (PhD Student)
Puja Mehta (Intern – Neurology Registrar)
Within UK DRI:
- Prof Chris Shaw, UK DRI at Kings
- Prof Kei Cho, UK DRI at Kings
- Prof Annalisa Pastore, UK DRI at Kings
- Dr Sarah Mizelinska, UK DRI at Kings
- Dr Marc-David Ruepp, UK DRI at Kings
- Prof Bart de Strooper, UK DRI at UCL
- Prof John Hardy, UK DRI at UCL
- Prof Tara Spires-Jones, UK DRI at Edinburgh
Beyond UK DRI:
- Prof Dag Aarsland, King’s College London
- Prof Pat Doherty, King’s College London
- Dr Claire Steves, King’s College London
- Dr Caroline Vance, King’s College London
- Prof Rosa Paolicelli, University of Lausanne, CH
- Dr Sally Cowley, University of Oxford
- Prof John Trojanowski, University of Pennsylvania, US
- Prof Virginia Lee, University of Pennsylvania, US
- Dr Paul Schultz, Baylor College of Medicine, US
- Dr Stanley Appel, Baylor College of Medicine, US
- Prof Rudiyanto Gunawan, ETH Zurich
- Prof Michaela Matteoli, Humanitas University, Italy
Alzheimer’s disease, amyloid, microglia, ageing, synapse
CRISPR/Cas9 screening, iPSC-derived microglia, primary microglia cell culture
7. Key publications
Rajendran L, Paolicelli RC. Microglia-Mediated Synapse Loss in Alzheimer's Disease. J Neurosci. 2018 Mar 21;38(12):2911-2919.
Paolicelli RC, Jawaid A, Henstridge CM, Valeri A, Merlini M, Robinson JL, Lee EB, Rose J, Appel S, Lee VM, Trojanowski JQ, Spires-Jones T, Schulz PE, Rajendran L. TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss. Neuron. 2017 Jul 19;95(2):297-308.e6.
Siegel G, Gerber H, Koch P, Bruestle O, Fraering PC, Rajendran L. The Alzheimer's Disease γ-Secretase Generates Higher 42:40 Ratios for β-Amyloid Than for p3 Peptides. Cell Rep. 2017 Jun 6;19(10):1967-1976.
Ben Halima S, Mishra S, Raja KMP, Willem M, Baici A, Simons K, Brüstle O, Koch P, Haass C, Caflisch A, Rajendran L. Specific Inhibition of β-Secretas Processing of the Alzheimer Disease Amyloid Precursor Protein. Cell Rep. 2016 Mar 8;14(9):2127-2141.
Bali J, Gheinani AH, Zurbriggen S, Rajendran L. Role of genes linked to sporadic Alzheimer's disease risk in the production of β-amyloid peptides. Proc Natl Acad Sci U S A. 2012 Sep 18;109(38):15307-11.
Aguzzi A, Rajendran L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron. 2009 Dec 24;64(6):783-90.
Rajendran L, Knölker HJ, Simons K. Subcellular targeting strategies for drug design and delivery. Nat Rev Drug Discov. 2010 Jan;9(1):29-42.
Rajendran L, Schneider A, Schlechtingen G, Weidlich S, Ries J, Braxmeier T, Schwille P, Schulz JB, Schroeder C, Simons M, Jennings G, Knölker HJ, Simons K. Efficient inhibition of the Alzheimer's disease beta-secretase by membrane targeting. Science. 2008 Apr 25;320(5875):520-3.
Rajendran L, Honsho M, Zahn TR, Keller P, Geiger KD, Verkade P, Simons K. Alzheimer's disease beta-amyloid peptides are released in association with exosomes. Proc Natl Acad Sci U S A. 2006 Jul 25;103(30):11172-7.