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Cellular phenotyping of hippocampal progenitors exposed to patient serum predicts conversion to Alzheimer’s Disease

Aleksandra Maruszak, Tytus Murphy, Benjamine Liu, Chiara de Lucia, Abdel Douiri, Alejo J Nevado, Charlotte E Teunissen, Pieter Jelle Visser, Jack Price, Simon Lovestone, View ORCID ProfileSandrine Thuret
doi: https://doi.org/10.1101/175604
Aleksandra Maruszak
1Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
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Tytus Murphy
1Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
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Benjamine Liu
3Department of Psychiatry, University of Oxford, UK
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Chiara de Lucia
1Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
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Abdel Douiri
2Department of Public Health Sciences, King’s College London, London, UK
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Alejo J Nevado
3Department of Psychiatry, University of Oxford, UK
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Charlotte E Teunissen
4Neurochemistry Lab and Biobank, Department of Clinical Chemistry, Amsterdam Neuroscience, VU University Medical Center, The Netherlands
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Pieter Jelle Visser
5Department of Psychiatry and Neuropsychology, Alzheimer Center Limburg, School for Mental Health and Neuroscience, Maastricht University, Maastricht, The Netherlands
6Department of Neurology, Alzheimer Center, VU University Medical Center, Amsterdam, The Netherlands
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Jack Price
1Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
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Simon Lovestone
3Department of Psychiatry, University of Oxford, UK
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Sandrine Thuret
1Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
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  • ORCID record for Sandrine Thuret
  • For correspondence: sandrine.1.thuret@kcl.ac.uk
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Abstract

The generation of new neurons persists into adulthood in the human hippocampus and can be modulated by the circulatory systemic environment. Hippocampal neurogenesis is important for learning and memory and is altered in Alzheimer’s Disease (AD). Evaluating the hippocampal neurogenic process during disease progression could therefore identify neurogenesis as an important target for AD prevention and intervention as well as a biomarker for early disease detection. In this study, we used a human hippocampal progenitor cell line to design an in vitro assay evaluating over time the neurogenic impact of the systemic milieu (i.e. serum) of individuals with mild cognitive impairment (MCI) as they either converted to AD or remained cognitively stable. Cells were exposed to serum collected over several years from the same patients. Cellular phenotyping and linear mixed effects models for repeated measures revealed that decreased proliferation, increased apoptotic hippocampal progenitor cell death and increased hippocampal neurogenesis characterized progression from MCI to AD. Using stepwise logistic regression and machine learning we show that these cellular readouts for the baseline serum sample and years of education of the patient are significant predictors of conversion from MCI to AD, already 3.5 years before AD clinical diagnosis. Finally, serum proteomic analyses indicated pathways linked to the cellular readouts distinguishing MCI to AD converters from non-converters. The proposed assay is thus not only promising for AD pre-clinical diagnosis, but it also provides a proxy into temporal changes of the hippocampal neurogenic process during disease progression.

One Sentence Summary In this study, we demonstrate for the first time that the systemic environment (i.e. blood serum) of mild cognitively impaired patients differentially alters human hippocampal progenitor cell fate to predict conversion to Alzheimer’s Disease up to 3.5 years before clinical diagnosis.

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Posted August 13, 2017.
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Cellular phenotyping of hippocampal progenitors exposed to patient serum predicts conversion to Alzheimer’s Disease
Aleksandra Maruszak, Tytus Murphy, Benjamine Liu, Chiara de Lucia, Abdel Douiri, Alejo J Nevado, Charlotte E Teunissen, Pieter Jelle Visser, Jack Price, Simon Lovestone, Sandrine Thuret
bioRxiv 175604; doi: https://doi.org/10.1101/175604
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Cellular phenotyping of hippocampal progenitors exposed to patient serum predicts conversion to Alzheimer’s Disease
Aleksandra Maruszak, Tytus Murphy, Benjamine Liu, Chiara de Lucia, Abdel Douiri, Alejo J Nevado, Charlotte E Teunissen, Pieter Jelle Visser, Jack Price, Simon Lovestone, Sandrine Thuret
bioRxiv 175604; doi: https://doi.org/10.1101/175604

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