title: 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.
authors.affiliation: Neuroscience Drug Discovery, Bristol-Myers Squibb, Wallingford, CT 06492, USA. donna.barten@bms.com
authors.forename: Donna M
authors.initials: DM
authors.lastname: Barten
authors.forename: Gregory W
authors.initials: GW
authors.lastname: Cadelina
authors.forename: Nina
authors.initials: N
authors.lastname: Hoque
authors.forename: Lynn B
authors.initials: LB
authors.lastname: DeCarr
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Guss
authors.forename: Ling
authors.initials: L
authors.lastname: Yang
authors.forename: Sethu
authors.initials: S
authors.lastname: Sankaranarayanan
authors.forename: Paul D
authors.initials: PD
authors.lastname: Wes
authors.forename: Marianne E
authors.initials: ME
authors.lastname: Flynn
authors.forename: Jere E
authors.initials: JE
authors.lastname: Meredith
authors.forename: Michael K
authors.initials: MK
authors.lastname: Ahlijanian
authors.forename: Charles F
authors.initials: CF
authors.lastname: Albright
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000473:pathology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004318:Doxycycline / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016900:Neurofilament Proteins / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000134:cerebrospinal fluid* / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers; D016900:Neurofilament Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger; C498585:TUBB3 protein, human; D014404:Tubulin; D016875:tau Proteins; C051774:neurofilament protein H; D004318:Doxycycline