Novel marker for the onset of frontotemporal dementia: early increase in activity-dependent neuroprotective protein (ADNP) in the face of Tau mutation.
Tauopathy, a major pathology in Alzheimer's disease, is also found in ~50% of frontotemporal dementias (FTDs). Tau transcript, a product of a single gene, undergoes alternative splicing to yield 6 protein species, each with either 3 or 4 microtubule binding repeat domains (tau 3R or 4R, associated with dynamic and stable microtubules, respectively). While the healthy human brain shows a 1/1 ratio of tau 3R/4R, this ratio may be dramatically changed in the FTD brain. We have previously discovered that activity-dependent neuroprotective protein (ADNP) is essential for brain formation in the mouse, with ADNP+/- mice exhibiting tauopathy, age-driven neurodegeneration and behavioral deficits. Here, in transgenic mice overexpressing a mutated tau 4R species, in the cerebral cortex but not in the cerebellum, we showed significantly increased ADNP expression (~3-fold transcripts) in the cerebral cortex of young transgenic mice (~disease onset), but not in the cerebellum, as compared to control littermates. The transgene-age-related increased ADNP expression paralleled augmented dynamic tau 3R transcript level compared to control littermates. Blocking mutated tau 4R transgene expression resulted in normalization of ADNP and tau 3R expression. ADNP was previously shown to be a member of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. Here, Brahma (Brm), a component of the SWI/SNF complex regulating alternative splicing, showed a similar developmental expression pattern to ADNP. Immunoprecipitations further suggested Brm-ADNP interaction coupled to ADNP - polypyrimidine tract-binding protein (PTB)-associated splicing factor (PSF)-binding, with PSF being a direct regulator of tau transcript splicing. It should be noted that although we have shown a correlation between levels of ADNP and tau isoform expression three months of age, we are not presenting evidence of a direct link between the two. Future research into ADNP/tau relations is warranted.
The Adams Super Center for Brain Studies, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Yulie
Y
Schirer
The Adams Super Center for Brain Studies, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Anna
A
Malishkevich
The Adams Super Center for Brain Studies, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Yotam
Y
Ophir
Center for Translational Research in Neurodegenerative Disease, University of Florida College of Medicine, Gainesville, Florida, United States of America.
Jada
J
Lewis
The Adams Super Center for Brain Studies, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Eliezer
E
Giladi
The Adams Super Center for Brain Studies, The Lily and Avraham Gildor Chair for the Investigation of Growth Factors, The Elton Laboratory for Neuroendocrinology, Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
Illana
I
Gozes
D000544:Alzheimer Disease / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D000072670:PTB-Associated Splicing Factor; D016601:RNA-Binding Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics*
C117632:Adnp protein, mouse; D015415:Biomarkers; D018398:Homeodomain Proteins; C558298:Mapt protein, mouse; D009419:Nerve Tissue Proteins; D000072670:PTB-Associated Splicing Factor; D016601:RNA-Binding Proteins; C499503:Smarca2 protein, mouse; D014157:Transcription Factors; D016875:tau Proteins