Tau Transgenic Mice as Models for Cerebrospinal Fluid Tau Biomarkers

Issue title: Drug Discovery for Neurodegenerative Diseases: Challenges and Novel Biochemical Targets

Guest editors: Gabriel B. Britton, Mark A. Smith, George Perry, Kumar Sambamurti and K.S. Jagannatha Rao

Article type: Research Article

Authors: Barten, Donna M.^{; *} | Cadelina, Gregory W. | Hoque, Nina | DeCarr, Lynn B. | Guss, Valerie L. | Yang, Ling | Sankaranarayanan, Sethu | Wes, Paul D. | Flynn, Marianne E. | Meredith, Jere E. | Ahlijanian, Michael K. | Albright, Charles F.

Affiliations: Neuroscience Drug Discovery, Bristol-Myers Squibb, Wallingford, CT, USA

Correspondence: [*] Correspondence to: Dr. Donna M. Barten, Neuroscience Drug Discovery, Bristol-Myers Squibb, 3CD-405, PO Box 5100, Wallingford, CT 06492, USA. Tel.: +1 203 677 6962; Fax: +1 203 677 7569; E-mail: donna.barten@bms.com.

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.

Keywords: Alzheimer's disease, cerebrospinal fluid, ELISA, FTDP-17 protein, human, MAPT, mice, tau proteins, tauopathy, transgenic

DOI: 10.3233/JAD-2011-110161

Journal: Journal of Alzheimer's Disease, vol. 24, no. s2, pp. 127-141, 2011