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.
1. Study the profile and mechanisms of known AD CSF 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 (APP, Tau, alpha- 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) nicely recapitulate changes of Aβ and tau in CSF observed in Alzheimer’s disease (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 recently succeeded to generate a novel high-sensitivity sandwich assay, which allowed us to study the effect of disease-modifying drugs on endogenous CSF and blood tau in APP transgenic mice. Using a strong BACE1 inhibitor we could demonstrate that 6 months of treatment completely abolished the age-related CSF tau increase, which is normally observed in these mice (Schelle et al., Alzheimers Dement, 2016). The tight correlation of cerebral Aβ deposition and CSF tau implied downstream effects of BACE1 inhibition, rendering CSF tau a pivotal biomarker for the assessment of long-term efficacy of BACE1 inhibitors in clinical trials.
We also found robust and consistent increases of neurofilament light chain (NfL) in CSF and blood in murine models of α-synucleinopathies, tauopathy, and ß-amyloidosis (Bacioglu and Maia et al., Neuron, 2016). Blood and CSF NfL levels were strongly correlated suggesting 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 and correlated in magnitude with 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: Seeded induction of α-synuclein inclusions in α-synuclein transgenic mice increased both CSF and blood NfL levels, while BACE1 inhibition in Aβ precursor protein transgenic mice reduced Aβ deposition and the concomitant increase of NfL in CSF and blood. Consistently, we also found NfL increases in human CSF and blood of α-synucleinopathies, tauopathies, and Alzheimer’s disease. These results show that the NfL changes in the CSF and excitingly also blood reflect the neurodegenerative process in the brain and can serve as a reliable and easily accessible biomarker to monitor disease progression and treatment response in mouse models and potentially also for human proteopathic neurodegenerative diseases.
Contact: Stephan Käser
Schelle J, Häsler L, Göpfert JC, Joos TO, Vanderstichele H, Stoops E, Mandelkow EM, Neumann U, Shimshek DR, Staufenbiel M, Jucker M, Kaeser SA (2016) Prevention of tau increase in cerebrospinal fluid of APP transgenic mice suggests downstream effect of BACE1 inhibition. Alzheimers Dement. doi: 10.1016/j.jalz.2016.09.005. [Epub ahead of print] (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: 251-261 (Abstract)