mRNA levels of BDNF in rodent models of HD

mRNA levels of BDNF decline with disease progression in rodent models of HD and are restored to normal levels by CEP-1347.

This study is companion research to CEP-1347 restores BDNF expression in the R6/2 mice . This second study suggests that levels of BDNF's messenger RNA in the blood might serve as biomarkers. While levels of the BDNF protein itself were not detectable in the blood, levels of mRNA were detectable in rodent models.  These levels declined with age but were restored to normal levels by CEP-1347 treatment.

If BDNF mRNA is also detectable in the blood of those who are gene positive, then it would be a good biomarker to determine when treatment is necessary and whether it has been effective in restoring BDNF. 

Marsha L. Miller, Ph.D.
Dr. Elena Cattaneo
Blood level of brain-derived neurotrophic factor mRNA is progressively reduced in rodent models of Huntington's disease: Restoration by the neuroprotective compound CEP-1347
Paola Conforti, Catarina Ramos, Barbara L. Apostol, Danielle A. Simmons, Huu Phuc Nguyen, Olaf Riessc, Leslie Michels Thompson, Chiara Zuccato and Elena Cattaneo
Huntington's disease (HD) is an age-related neurodegenerative disorder that is currently untreatable. A prominent feature of HD pathology is the reduction of the pro-survival neurotrophin Brain-Derived Neurotrophic Factor (BDNF). Both mRNA and protein levels of BDNF are decreased in the brains of several HD rodent models and in human HD patients. We now report for the first time that this molecular event is mirrored in blood from HD rodent models. While protein levels of BDNF are undetectable in mouse blood, mRNA levels are measurable and diminish during HD progression in transgenic mouse (R6/2) and rat models of HD. Among the eight different BDNF transcripts, only BDNF exon III is transcribed in mouse blood and its expression is progressively compromised in R6/2 mice with respect to age-matched wild-types. Assessment of BDNF mRNA in HD rat blood shows a similar result, which is reinforced by evidence that protein levels of the neurotrophin are also significantly reduced at a symptomatic stage. Finally, we demonstrate that acute and chronic treatment of R6/2 mice with CEP-1347, a mixed lineage kinase (MLK) inhibitor with neuroprotective and neurotrophic effects, leads to increased total BDNF mRNA in blood when compared to untreated R6/2 mice. Our results indicate that alterations in BDNF mRNA levels in peripheral blood are a readily accessible measurement of disease progression and drug efficacy in HD rodent models.
Molecular and Cellular Neuroscience 2008 May 10. [Epub ahead of print]