Suppression of tau increase in cerebrospinal fluid of app transgenic mice provides evidence for downstream effect of bace1 inhibition

The best-validated and established fluid biomarkers for Alzheimer's disease (AD) are reduced Abeta42 and increased tau levels in the cerebrospinal fluid (CSF). We have previously shown that this CSF signature is mirrored in aging Abeta precursor protein (APP) transgenic mice. Despite the lack of neurofibrillary tangles and global neuron loss, they exhibit higher CSF tau concentrations with progressing plaque deposition, indicating that beta-amyloidosis is a major trigger for CSF tau increase. Moreover it suggests that APP transgenic mouse models can be instrumental to predict CSF biomarker changes in clinical trials directed against Abeta. One of the main therapeutic approaches tested for the treatment of AD is the inhibition of the beta-site amyloid precursor protein-cleaving enzyme 1 (BACE1). We now used a potent BACE1 inhibitor to treat early-depositing APPPS1 and APP23 mice during six months and evaluated CSF tau changes. For the accurate quantification of murine tau we developed a novel high-sensitivity assay based on the single molecule array (Simoa) technology. In addition, we measured Abeta42 and 40 in the CSF and brain tissue of the same mice and assessed their plaque load by stereological analysis on histological brain sections. As expected, long-term BACE1 inhibition attenuated amyloid deposition in both APP transgenic mouse models. Strikingly, the CSF tau increase, which is normally seen without treatment, was completely abolished. CSF Abeta42 and 40 were reduced compared to baseline levels, which was already evident after one week of BACE1 inhibition. CSF tau concentration however, was unaffected after short-term treatment, accentuating again its link to amyloid plaque load. The prevention of CSF tau increase in two different APP transgenic mouse models suggests that BACE1 inhibition also affects down-stream AD pathologies. The strong correlation between CSF tau and cerebral amyloid renders CSF tau a useful marker for the monitoring of the effectiveness of a BACE1 inhibitor in current clinical trials. S.A.K. and J.S. contributed equally to this work.