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Molecular Biomarker Unit

Processes related to Alzheimer's disease (AD) and other age-related neurodegenerative diseases start many years before the onset of the first clinical symptoms. At the moment of the first clinical complaints, the disease has already caused severe brain damage. Thus, there is a critical need to characterize this pre-clinical disease stage and to identify patients at risk. In the absence of clinical features, disease biomarkers are crucial to define pre-symptomatic disease stages and to monitor the efficacy of an early treatment, aiming to stop the disease before the emergence of irreversible neurological impairments. Cerebrospinal fluid (CSF) and/or blood proteome constitute an appealing source for such biomarkers that can act as reliable predictors and indicators of the disease process.

Main objectives
Recent results
Staff
Publications

1. Study the profile and mechanisms of known AD CSF and blood biomarker changes (Aß and Tau) in patients and mouse models

2. Identify novel fluid biomarkers of neurodegeneration and neuroinflammation in mouse models and assess their value in the clinical setting

3. Use mouse models to predict and understand biomarker changes in response to treatments in clinical trials

To this end we have improved CSF and blood collection techniques in mice to meet the standards of the most recent QC programs for collecting and processing human samples (Mattson et al., Alz & Dem, 2013). Murine fluid samples are obtained from our aging colonies of mouse models of neurodegenerative diseases (e.g. α-synuclein transgenic mice). Human fluid samples are obtained from the Neuro-Biobank of the University Clinic and the DZNE Tübingen and in close collaboration with the Section for Dementia Research. Highly sensitive multiplex immunoassays are used and cross-validated with current ELISA, ECL- or bead-based techniques.

We have reported that mice overexpressing human β-amyloid precursor protein (APP) recapitulate changes of Aβ and tau in CSF observed in Alzheimer’s disease (AD) (Maia and Kaeser et al., Science Transl Med, 2013). This work laid the foundation to use transgenic mouse models for translational research of fluid biomarkers.

We then succeeded to generate a novel high-sensitivity sandwich assay to measure endogenous tau in CSF and blood of APP transgenic mice. Using a strong BACE1 inhibitor, we could demonstrate that reduction of Aß generation completely abolished the age-related CDF tau increase in these mice (Schelle et al., Alzheimers Dement, 2016). These findings (Maia and Kaeser et al., Science Transl Med, 2013; Schelle et al., Alzheimers Dement, 2016) and the tight correlation of cerebral Aβ deposition with CSF tau suggests that CSF tau is a biomarker of Aß deposition in brain (rather than for tau lesions as previously thought).

We also established neurofilament light chain (NfL) in CSF and blood in mice as a marker of neurodegeneration. Robust increases of NfL in CSF and blood were found in murine models of α-synucleinopathies, tauopathy, and ß-amyloidosis (Bacioglu et al., Neuron, 2016). Blood and CSF NfL levels were strongly correlated demonstrating that most of the NfL in blood derives from the CNS. The increases of NfL in CSF and blood in the mouse models coincided with the onset of the corresponding proteopathic lesions in brain. To mechanistically link the brain proteopathic lesions to the NfL changes in bodily fluids we experimentally induced and blocked the lesions: Induction of proteopathic lesions in α-synuclein transgenic mice increased both CSF and blood NfL levels, whereas reduction of Aß deposition through BACE1 inhibition in APP transgenic mice attenuated the NfL increase. Consistently, we also found NfL increases in human CSF and blood of α-synucleinopathies, tauopathies, and AD (Bacioglu et al., Neuron, 2016). Exploiting the biospecimes of the DIAN study, we found that NfL in blood predicts disease progression already at very early presymptomatic stages of familial AD, which supports the great potential of NfL as a clinically useful blood biomarker for neurodegeneration (Preische et al., Nature Medicine, 2019).


 
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Department
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Email

Preische O, Schultz SA, Apel A, Kuhle J, Kaeser SA, Barro C, Gräber S, Kuder-Buletta E, LaFougere C, Laske C, Vöglein J, Levin J, Masters CL, Martins R, Schofield PR, Rossor MN, Graff-Radford NR, Salloway S Ghetti B, Ringman JM, Noble JM, Chhatwal J, Goate AM, Benzinger TLS, Morris JC, Bateman RJ, Wang G, Fagan AM, McDade EM, Gordon BA, Jucker M; Dominantly Inherited Alzheimer Network (2019) Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease. Nature medicine 25(2):277-283 (Abstract)

Schelle J, Häsler L, Göpfert JC, Joos TO, Vanderstichele H, Stoops E, Mandelkow EM, Neumann U, Shimshek DR, Staufenbiel M, Jucker M, Kaeser SA (2017) Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimers Dement 13:701-9 (Abstract)

Bacioglu M, Maia LF, Preische O, Schelle J, Apel A, Kaeser SA, Schweighauser M, Eninger T, Lambert M, Pilotto A, Shimshek DR, Neumann U, Kahle PJ, Staufenbiel M, Neumann M, Maetzler W, Kuhle J, Jucker M (2016) Neurofilament Light Chain in Blood and CSF as Marker of Disease Progression in Mouse Models and in Neurodegenerative Diseases. Neuron 91:56-66 (Abstract)

Maia LF, Kaeser SA, Reichwald J, Lambert M, Obermüller U, Odenthal J, Martus P, Staufenbiel M, Schelle J, Jucker M (2015) Increase of CSF Aß during the very early phase of cerebral Aß deposition in mouse models. EMBO Mol Med 7:895-903 (Abstract)

Maia LF, Kaeser SA, Reichwald J, Hruscha M, Martus P, Staufenbiel M, Jucker M (2013) Changes in Amyloid-β and Tau in the Cerebrospinal Fluid of Transgenic Mice Overexpressing Amyloid Precursor Protein. Sci Transl Med 5:194re2 (Abstract)

Mattsson N, Andreasson U, Persson S, Carrillo MC, Collins S, Chalbot S, Cutler N, Dufour-Rainfray D, Fagan AM, Heegaard NH, Robin Hsiung GY, Hyman B, Iqbal K, Lachno DR, Lleó A, Lewczuk P, Molinuevo JL, Parchi P, Regeniter A, Rissman R, Rosenmann H, Sancesario G, Schröder J, Shaw LM, Teunissen CE, Trojanowski JQ, Vanderstichele H, Vandijck M, Verbeek MM, Zetterberg H, Blennow K, Käser SA; Alzheimer's Association QC Program Work Group. (2013) CSF biomarker variability in the Alzheimer's Association quality control program. Alzheimers Dement 9: 251-61 (Abstract)

Contact
Stephan Käser stephan.kaeseruni-tuebingen.de Address

Center of Neurology
Hertie Institute for Clinical Brain Research
Department Cellular Neurology

Otfried-Müller-Straße 27
72076 Tübingen

Phone: +49 (0)7071 29-86855
Fax: +49 (0)7071 29-4521

list of publications