Alzheimer´s: disease-associated biomarker changes in cerebrospinal fluid of transgenic mice

The new research suggests that AD in its earliest stage already causes changes in CSF-levels of tau and amyloid-beta and that these changes are both the results of the build-up of the amyloid-beta protein in brain, which is characteristic for the disease.

This study opens new perspectives on the use of these mouse models in translational research say the senior authors of the study Mathias Jucker and Matthias Staufenbiel. In particular, in therapy trials of sporadic and familial AD the mouse models should be instrumental to predict the CSF changes in patients. They also could help to discover new early biomarkers in CSF and other bodily fluids.

Processes related to AD start at least 10 to 20 years before the onset of the first clinical symptoms. At the moment of diagnosis, the disease has already caused severe brain damage. Thus, there is a critical need to characterize this pre-clinical stage of the disease and to identify patients at risk well ahead of any clinical complaint. This is particularly crucial for early treatment aiming to stop the disease before the emergence of irreversible symptoms and signs. Biomarkers could act as reliable predictors and indicators of a disease process. They offer one of the most promising paths, when it comes to early AD-diagnosis. Biomarkers include proteins in blood or spinal fluid, genetic variations (mutations) or brain changes detectable by imaging.

Very early biomarkers in humans that show changes at least a decade before AD symptoms are noted, can be found in the cerebrospinal fluid (CSF). In the CSF the amyloid-beta protein is decreased while the tau protein is increased. The causes for these CSF changes have been largely speculative mainly because of the lack of useful animal models that also mimic these changes.

In order to tackle this point, the scientists first developed highly-sensitive methods to reliably assess amyloid-beta and tau in AD transgenic mice (these mice develop amyloid plaques, one hallmark of the Alzheimer’s pathology in the brain). Then, by assessing amyloid-beta and tau at different time points the authors could show that amyloid-beta goes down in the CSF after the first amyloid plaques appear in the brain and, remarkably, this decrease in amyloid-beta is followed by an increase in tau in the cerebrospinal fluid. The latter is notable, because the mice neither develop the second hallmark of AD pathology, namely the tau deposits, so called neurofibrillary tangles, nor global neuronal loss. Thus it is shown for the first time that the increase of tau in the CSF can occur independently of neurofibrillary tangles or frank neuron loss (as these do not occur in the mouse models used).

Citation
L. F. Maia, S. A. Kaeser, J. Reichwald, M. Hruscha, P. Martus, M. Staufenbiel, M. Jucker

Changes in amyloid-b and Tau in the cerebrospinal fluid of transgenic mice overexpressing amyloid precursor protein. Sci. Transl. Med. 5, 194rexx (2013)