Tau Transgenic Mice as Models for Cerebrospinal Fluid Tau Biomarkers

Abstract

Levels of tau in cerebrospinal fluid (CSF) are elevated in Alzheimer's disease (AD) patients. It is believed this elevation is related to the tau pathology and neurodegeneration observed in AD, but not all tauopathies have increased CSF tau. There has been little pre-clinical work to investigate mechanisms of increased CSF tau due to the difficulty in collecting CSF samples from mice, the most commonly used pre-clinical models. We developed methods to collect CSF from mice without contamination from tau in brain tissue, which is approximately 50,000 fold more abundant in brain than CSF. Using these methods, we measured CSF tau from 3xTg, Tg4510, and Tau Alone transgenic mice. All three lines of mice showed age-dependent increases in CSF tau. They varied in phenotype from undetectable to severe tau pathology and neurodegeneration, suggesting that degenerating neurons are unlikely to be the only source of pathologic CSF tau. Overall, CSF tau levels mirrored expression levels and changes of tau in the brain, but they did not always correlate exactly. CSF tau was often more sensitive to changes in brain transgene expression and pathology. In addition, we also developed ELISA assays specific to different regions of the tau protein. We used these assays to provide evidence that CSF tau exists as fragments, with little intact C-terminus and partial loss of the N-terminus. Taken together, these assays and mouse models may be used to facilitate a deeper understanding of CSF tau in neurodegenerative disease.

Hyperdynamic Microtubules, Cognitive Deficits, and Pathology Are Improved in Tau Transgenic Mice with Low Doses of the Microtubule-Stabilizing Agent BMS-241027

“…2 D). Tau-P301L transgene expression can be reduced 75% in rTg4510 mice with doxycycline treatment Barten et al, 2011), which was also observed in this study by immunohistochemical staining of tau (Fig. 3A).…”

“…Abnormal MT turnover in the two transgenic lines was generally consistent with the level of tau pathology not just total tau protein levels. 3xTg mice have approximately twofold overexpression of the tau-P301L transgene and much less pathology than the 13-fold overexpressing rTg4510 line Barten et al, 2011). Even so, Tau Alone transgenic mice have leaky transgene expression from the TRE promoter that is close to the amount observed in 3xTg mice.…”

“…Immunohistochemistry on paraffin-embedded sections was performed as described previously (Barten et al, 2011). AT8 and AT180 were obtained from Thermo Scientific, anti-pTau181 antibody Anaspec, MC-1 from Peter Davies (Albert Einstein College of Medicine, Bronx, NY), anti-GFAP polyclonal antibody from Dako, and anti-Iba1 polyclonal antibody from Wako.…”

“…Mice were housed with a 6:00 A.M. to 6:00 P.M. light/dark cycle and allowed free access to food and water. For doxycycline treatment, mice were fed chow containing 200 ppm doxycycline (Barten et al, 2011). BMS-241027 was dosed intraperitoneally once weekly, in 10% ethanol, 90% water, or in 8.5% polyethylene glycol, average molecular weight of 400, 1% D-␣-tocopheryl polyethylene glycol 1000 succinate, 0.5% ethanol, 90% water.…”

Transmission of Tau Pathology from Human to Rodent Brain: How to Humanise Animal Models for Alzheimer’s Disease Research

“…Tau is constitutively released from neurons under physiological conditions [71,[76][77][78][79][80][81][82][83][84][85][86][87][88]. The secretion is multifaceted, involving diverse intracellular components such as autophagosomes, Golgi, endosomes, ectosomes, lysosomes, microsomes and endoplasmic reticulum [89]. In the diseased brain, extracellular tau additionally originates from dead or dying neurons as well as a result of active secretion [76,90] and yet unknown mechanisms.…”