"Dementia is one of the biggest problems our world faces and I am excited to be working towards defeating it with the backing of the UK DRI." Cara Croft
UK DRI Emerging Leader
After obtaining her PhD in Neuroscience from King’s College London in 2016, Dr Cara Croft joined the University of Florida for her postdoctoral training and Brightfocus Foundation postdoctoral fellowship, where she was also awarded the McKnight Leadership Award in 2020 for contributions to neuroscience research, education and outreach. With a prestigious Race Against Dementia fellowship, she joined the UK DRI at UCL in 2021 as a UK DRI Emerging Leader – sponsored by Prof Bart De Strooper. Dr Croft aims to understand how known risk genes link to the development of signature disease pathologies and neurodegeneration in dementia, and whether these processes can be targeted by new treatments.
1. At a glance
Alzheimer's disease (AD), frontotemporal dementia (FTD), Parkinson’s disease (PD) and Lewy body dementia (LBD) are the most common causes of dementia leading to loss of memory and thoughts and other symptoms. Scientists know that changes in proteins in these diseases cause them to buildup inside brain cells eventually resulting in them dying. Scientists have also discovered that changes in genes can increase the risk of a person getting dementia, but we do not know how these genetic changes may affect the buildup of these proteins to cause dementia. Dr Croft is investigating how several of these genetic risks impact the protein buildup and how they affect the death of brain cells, using a system that keeps small sections of mouse brain tissue alive that develop the buildup of these proteins we see in disease. By using this model, Dr Croft aims to accelerate our understanding of how these genetic risk factors affect protein buildup and brain cell death. She will then expand these studies into animal models, to predict whether people with dementia can be helped in the future by targeting this protein accumulation or these genetic pathways.
2. Scientific goals
Alzheimer's disease (AD), Frontotemporal dementia (FTD), Parkinson’s disease (PD) and Lewy body dementia (LBD) represent the most common causes of dementia. Numerous gene loci have been linked to these diseases, although the majority have not been well studied. Indeed, many mechanisms underlying these diseases remain enigmatic, and therapeutic development has not progressed as rapidly as many had hoped. Translation has been somewhat limited by immature in vitro models that do not represent the milieu of intact brain and the slow throughput of available in vivo models.
To address the niche for advanced in vitro models, Dr Croft has established novel organotypic brain slice culture (BSC) models of mature tau and α-synuclein inclusion pathologies transduced by recombinant adenoassociated viruses (rAAVs). These models potentially provide a physiologically and functionally relevant system to rapidly pre-screen before in vivo studies. Dr Croft aims to test the predictive value of this system alongside a panel of novel rAAVs to be developed. Her project will provide insight into how disease associated genes can modulate tau or α-synuclein pathologies linked with disease progression and neurodegeneration and potentially elucidate novel therapeutic targets.
These experiments will develop technology which can transform our understanding of how genetic risk factors can alter tau or α-synuclein burden and provide much-needed insight into novel therapeutic targets for these dementias. The proposed experiments using pre-screening in BSC models followed by more comprehensive screening of ‘hits’ in vivo enables us to assess the effects of multiple genetic risk factors in an accelerated manner with a moving target guided by initial studies. The planned experiments are ambitious, but the proposed pipeline will a) stratify which genes should be focused on in future studies, b) develop technology to provide functional and mechanistic insights, c) identify which pathways could be therapeutically targeted and d) inform our understanding of these diseases.
Main objectives and research goals:
1. Systematically screen the effects of multiple associated genetic risk factors on tauopathy.
2. Assess the effects of multiple associated genetic risk factors on α-synucleinopathy.
3. Team members
Lyla Rowe (Research Assistant)
Within UK DRI:
- Dr Patricio Opazo, UK DRI at University of Edinburgh
Beyond UK DRI:
- Prof Todd Golde, University of Florida
- Dr Wendy Noble, King’s College London
Alzheimer’s disease, Parkinson’s disease, Protein Aggregation, Tau, alpha-synuclein, risk genes
Viral vector design and production, mammalian models, in vivo imaging, organotypic cultures, CRISPR/Cas9
7. Key publications
Croft, C.L., Goodwin, M.S., Ryu, D.H., Lessard, C.B., Tejeda, G., Marrero, M., ...Lewis, J. (2021). Photodynamic studies reveal rapid formation and appreciable turnover of tau inclusions. Acta Neuropathologica, doi:10.1007/s00401-021-02264-9
Goodwin, M.S., Croft, C.L., Futch, H.S., Ryu, D., Ceballos-Diaz, C., Liu, X., ...Menezes, K. (2020). Utilizing minimally purified secreted rAAV for rapid and cost-effective manipulation of gene expression in the CNS. Molecular Neurodegeneration, 15 (1), doi:10.1186/s13024-020-00361-z
Croft, C.L., Cruz, P.E., Ryu, D.H., Ceballos-Diaz, C., Strang, K.H., Woody, B.M., ...Dickson, D.W. (2019). rAAV-based brain slice culture models of Alzheimer's and Parkinson's disease inclusion pathologies. JOURNAL OF EXPERIMENTAL MEDICINE, 216 (3), 539-555. doi:10.1084/jem.20182184
Croft, C.L., Moore, B.D., Ran, Y., Chakrabarty, P., Levites, Y., Golde, T.E., Giasson, B.I. (2018). Novel monoclonal antibodies targeting the microtubule-binding domain of human tau.. PLoS One, 13 (4), e0195211. doi:10.1371/journal.pone.0195211
Strang, K.H., Croft, C.L., Sorrentino, Z.A., Chakrabarty, P., Golde, T.E., Giasson, B.I. (2018). Distinct differences in prion-like seeding and aggregation between Tau protein variants provide mechanistic insights into tauopathies. JOURNAL OF BIOLOGICAL CHEMISTRY, 293 (7), 2408-2421. doi:10.1074/jbc.M117.815357
Croft, C.L., Wade, M.A., Kurbatskaya, K., Mastrandreas, P., Hughes, M.M., Phillips, E.C., ...Noble, W. (2017). Membrane association and release of wild-type and pathological tau from organotypic brain slice cultures. Cell Death and Disease, 8 (3), doi:10.1038/cddis.2017.97