"I anticipate that my UK DRI programme will bring clarity to the roles of complement in neurodegeneration and identify ways in which complement modulation can be used to impact disease at least in a subset of at risk or early Alzheimer's disease patients." Paul Morgan
UK DRI Group Leader
Prof Paul Morgan is a leading researcher in the role of complement and other inflammatory pathways in disease, with over 30 years of experience in the field. Graduating in Medicine from Cardiff University, he went on to complete a PhD on the 'Biochemistry and Pathology of Complement Component C9', before completing postdoctoral training at Johns Hopkins Medical School in the US. He has been President of the International Complement Society (2011-14), and was elected Fellowship of Academia Europaea in 2015. As a Group Leader at the UK DRI at Cardiff, he will lead vital research on the complement system in Alzheimer’s disease.
1. At a glance
Complement – a help or hindrance in Alzheimer’s disease?
Alzheimer’s disease (AD) is the most common cause of dementia, accounting for around two-thirds of cases in older people. Although researchers don’t yet fully understand what triggers the disease, the build-up of toxic protein aggregates or 'clumps' in the brain is thought to be involved in driving its progression – causing damage and death to neurons.
For many years, the brain was thought to be ‘sealed’ from the rest of the body’s immune system by the blood-brain-barrier – preventing the entry of immune cells and molecules. However, scientists now appreciate various immune processes do operate within the brain and two-way communication, between here and the rest of the body, does occur. For instance, key immune proteins known as ‘complement’ are activated in the brains of people with AD. But scientists don’t fully understand the consequences - on one hand, this may help with waste clearance and prevent the build-up of toxic proteins while on the other, it could promote inflammatory responses that help drive disease progression.
Prof Paul Morgan is investigating exactly how complement contributes to AD development. His results will support the development of new tests that can help identify people with increased risk of developing AD or detect the disease early when interventions may be more effective. It will also inform the discovery of new drugs that can prevent or treat the condition by targeting complement.
2. Scientific goals
Gene discovery has implicated innate immunity, inflammation and the complement system as drivers of pathology in Alzheimer’s disease (AD). The involvement of complement is further supported by a large and growing body of evidence from animal studies, human biomarker and immunopathology findings and molecular pathway analyses.
Prof Paul Morgan’s recent work has identified plasma complement biomarkers predictive of AD; showing that plasma levels of complement proteins and activation markers in mild cognitively impaired (MCI) individuals are highly predictive of progression to AD, suggesting that complement is involved early in the disease process. These same complement biomarkers mirrored the polygenic risk score for AD, linking genetics to proteins. Complement also overlaps with and strongly influences other gene-implicated pathways such as phagocytosis, membrane turnover and debris removal, placing it at a nexus in the disease process and flagging as a potential target for therapeutic intervention.
Understanding precisely how complement contributes to the disease process in AD, a prerequisite for effective targeting, has been challenging. A simplistic interpretation might be that complement activation drives pathology by amplifying inflammation, activating glia and exacerbating neuronal damage; however, there is compelling evidence that complement activation can, in some circumstances, reduce or reverse AD pathology – the double-edged sword. For example, strategies that aim to enhance amyloid clearance using antibodies or immunisation rely on complement activation to opsonise amyloid for phagocytic removal, while in mouse AD models, complement C3 deficiency exacerbates disease in some and ameliorates in others.
This ambitious programme from Paul’s lab builds on recent findings and local strengths in gene discovery, brain imaging and drug development to achieve an understanding of the roles of complement at different stages of disease progression in AD models and patients. This detailed understanding will support the discovery of predictive biomarkers and guide the development of safe and effective anti-complement drugs for the prevention and therapy of AD.
Main objectives and research goals:
1. To explore the impact of AD-associated complement gene polymorphisms. Identifying mechanisms by which risk variants impact complement component expression and/or function and predispose to AD.
2. To analyse the ex vivo effects of complement on neuronal/synaptic health and phagocytosis. Characterisation of the effects of complement activation and regulation on synapses using cultured murine synaptosomes and synaptoneurosomes.
3. To carry out an in vivo characterisation of complement roles in disease development. Identifying roles of complement in driving pathology in AD mouse models using a combination of gene deletion and pharmacological interventions.
3. Team members
Dr Wioleta Zelek (Emerging Leader)
Dr Izzeddin Alsalahat (Postdoctoral Researcher)
Dr Sarah Carpanini (Postdoctoral Researcher)
Dr Nikoleta Daskoulidou (Postdoctoral Researcher)
Dr Timothy Hughes (Postdoctoral Researcher)
Dr Lewis Watkins (Postdoctoral Researcher)
Joel Punter (PTY student)
Within UK DRI:
- Prof Bart De Strooper, UK DRI at UCL
- Prof Henrik Zetterberg, UK DRI at UCL
- Prof Siddharthan Chandran, UK DRI at Edinburgh
Beyond UK DRI:
- GlaxoSmithKline (GSK) - collaborating on generating and testing agents to identify ‘hits’ that impact on disease progression in model systems.
- Janssen Pharmaceutica – collaborating on roles of complement in Parkinson’s disease models and prospect of using anti-complement drugs.
- ARUK Alzheimer Drug Discovery Unit, Oxford – collaborating on discovery of new complement-blocking brain-penetrant drugs.
Inflammation, neuroinflammation, synaptic health, complement, animal models
Mouse models, iPS-derived microglia, murine synaptosome and synaptoneurosome isolation
7. Key publications
Cooze BJ, Dickerson M, Loganathan R, Watkins LM, Grounds E, Pearson BR, Bevan RJ, Morgan BP, Magliozzi R, Reynolds R, Neal JW, Howell OW. The association between neurodegeneration and local complement activation in the thalamus to progressive multiple sclerosis outcome. Brain Pathol. 2022 Feb 7:e13054. doi: 10.1111/bpa.13054.
Carpanini SM, Torvell M, Bevan RJ, Byrne RAJ, Daskoulidou N, Saito T, Saido TC, Taylor PR, Hughes TR, Zelek WM, Morgan BP. Terminal complement pathway activation drives synaptic loss in Alzheimer's disease models. Acta Neuropathol Commun. 2022 Jul 6;10(1):99. doi: 10.1186/s40478-022-01404-w.
Gytz Olesen H, Michailidou I, Zelek WM, Vreijling J, Ruizendaal P, de Klein F, Marquart JA, Kuipers TB, Mei H, Zhang Y, Ahasan M, Johnson KK, Wang Y, Morgan BP, van Dijk M, Fluiter K, Andersen GR, Baas F. Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex. J Innate Immun. 2022 May 12:1-21.
Stevenson-Hoare J, Heslegrave A, Leonenko G, Fathalla D, Bellou E, Luckcuck L, Marshall R, Sims R, Morgan BP, Hardy J, de Strooper B, Williams J, Zetterberg H, Escott-Price V. Plasma biomarkers and genetics in the diagnosis and prediction of Alzheimer's disease. Brain. 2022 Apr 6:awac128. doi: 10.1093/brain/awac128. Epub ahead of print.
Zelek WM, Morgan BP. Targeting complement in neurodegeneration: challenges, risks, and strategies. Trends Pharmacol Sci. 2022 Aug;43(8):615-628.
Carpanini SM, Harwood JC, Baker E, Torvell M, The Gerad Consortium, Sims R, Williams J, Morgan BP. (2021). The Impact of Complement Genes on the Risk of Late-Onset Alzheimer's Disease. Genes (Basel). 12(3):443.
Byrne RAJ, Torvell M, Daskoulidou N, Fathalla D, Kokkali E, Carpanini SM, Morgan BP. (2021). Novel Monoclonal Antibodies Against Mouse C1q: Characterisation and Development of a Quantitative ELISA for Mouse C1q. Mol Neurobiol. 58(9):4323-4336. doi: 10.1007/s12035-021-02419-5.
Torvell M, Carpanini SM, Daskoulidou N, Byrne RAJ, Sims R, Morgan BP. (2021). Genetic Insights into the Impact of Complement in Alzheimer's Disease. Genes (Basel). 2021 Dec 15;12(12):1990. doi: 10.3390/genes12121990.
Bevan RJ, Hughes TR, Williams PA, Good MA, Morgan BP, Morgan JE. (2020). Retinal ganglion cell dendritic pruning as a marker of CNS degeneration across three mouse models of Alzheimer’s disease. Acta Neuropathol Comm Dec 7;8(1):216.
Jackson HM, Foley KE, O'Rourke R, Stearns TM, Fathalla D, Morgan BP, Howell GR. (2020). A novel mouse model expressing human forms for complement receptors CR1 and CR2. BMC Genet. 9;21(1):101.
Morgan AR, Touchard S, Leckey C, O'Hagan C, Nevado-Holgado AJ; NIMA Consortium, Barkhof F, Bertram L, Blin O, Bos I, Dobricic V, Engelborghs S, Frisoni G, Frölich L, Gabel S, Johannsen P, Kettunen P, Kłoszewska I, Legido-Quigley C, Lleó A, Martinez-Lage P, Mecocci P, Meersmans K, Molinuevo JL, Peyratout G, Popp J, Richardson J, Sala I, Scheltens P, Streffer J, Soininen H, Tainta-Cuezva M, Teunissen C, Tsolaki M, Vandenberghe R, Visser PJ, Vos S, Wahlund LO, Wallin A, Westwood S, Zetterberg H, Lovestone S, Morgan BP; Annex: NIMA–Wellcome Trust Consortium for Neuroimmunology of Mood Disorders and Alzheimer's Disease. Inflammatory biomarkers in Alzheimer's disease plasma. Alzheimers Dement. 2019 Jun;15(6):776-787. doi: 10.1016/j.jalz.2019.03.007
Kopczynska M, Zelek WM, Vespa S, Touchard S, Wardle M, Loveless S, Thomas RH, Hamandi K, Morgan BP. Complement System Biomarkers in Epilepsy. Seizure 2018; 60: 1-7.
Morgan BP. Complement in the pathogenesis of Alzheimer’s Disease. Semin Immunopathol 2018; 40(1):113-124.
Baker E, Sims R, Leonenko G, Frizzati A, Harwood J, Grozeva D, Genetic and Environmental Risk in Alzheimer's Disease (GERAD) Consortium, PERADES consortium, IGAP consortia, Morgan K, Passmore P, Holmes C, Powell J, Brayne C, Gill M, Mead S, Heun R, Bossu P, Spalletta G, Goate A, Cruchaga C, van Duijn C, Maier W, Ramirez A, Jones L, Hardy J, Ivanov D, Hill M, Holmans P, Allen N, Morgan P, Williams J, Escott-Price V. Gene based Analysis in HRC Imputed Genome Wide Association Data Identifies Three Novel Genes for Alzheimer's Disease. BioRxiv; Preprint; doi:https://doi.org/10.1101/374876