Novel Marker for the Onset of Frontotemporal Dementia: Early Increase in Activity-Dependent Neuroprotective Protein (ADNP) in the Face of Tau Mutation

Abstract

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 Compassionate Side of Neuroscience: Tony Sermone’s Undiagnosed Genetic Journey—ADNP Mutation

“…Using biochemical and cell biology techniques, we showed multiple crucial interactions for ADNP, including the chromatin remodeling complex SWI/SNF , the RNA splicing machinery (Schirer et al 2014), protein translation (Malishkevich et al 2015), as well as the microtubule (Oz et al 2014) and autophagy systems (Merenlender-Wagner et al 2015). However, no good science can exist without listening and watching the society needs and hearing out the parents and wonderful caretakers of the ADNP children, which follows herein (Sandra Bedrosian Sermone, Our Undiagnosed Genetic Journey-ADNP mutation, 2015).…”

Microtubule-Tau Interaction as a Therapeutic Target for Alzheimer’s Disease

“…ADNP is a member of the SWI/SNF chromatin remodeling complex , which is associated with transcription and splicing (Batsche et al 2006). ADNP expression was previously shown to be correlated with tau 3R expression (Schirer et al 2014). We also showed a direct interaction of ADNP with protein associated splicing factor (PSF) (Schirer et al 2014), which was found to associate with the SWI/SNF-like complex (Ito et al 2008) and also with tau splicing.…”

“…ADNP expression was previously shown to be correlated with tau 3R expression (Schirer et al 2014). We also showed a direct interaction of ADNP with protein associated splicing factor (PSF) (Schirer et al 2014), which was found to associate with the SWI/SNF-like complex (Ito et al 2008) and also with tau splicing. PSF suppresses tau exon 10 inclusion by interacting with a stem-loop structure downstream of exon 10 (Ray et al 2011).…”

In vivo and in vitro ketamine exposure exhibits a dose-dependent induction of activity-dependent neuroprotective protein in rat neurons

“…Alternatively the calcium dysregulation or kinase activation in response to ketamine might also alter tau splice forms. An alteration in tau isoforms with an increase in the tau isoform with four microtubule binding domains increased expression of ADNP (Schirer et al, 2014). Thus ketamine might alter the tau isoform ratios, which then signal of neurodegeneration and/or stress to the neuron.…”

“…Even mice with only half the concentration of ADNP demonstrate increased neurodegeneration with increased age (Vulih-Shultzman et al, 2007). ADNP's mechanism of action may be a regulator of gene transcription during early development (Pinhasov et al, 2003) or a regulator of splicing and transcription through its potential binding with heterochromatin protein (HP) 1a and Brahma (Brm), a component of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex (Schirer et al, 2014). Additional evidence for ADNP's function correlated a human mutation in exon 5 of ADNP with autism and increased expression of ADNP-1 and ADNP-2 mRNA (Helsmoortel et al, 2014).…”