Sexual divergence in activity-dependent neuroprotective protein impacting autism, schizophrenia, and Alzheimer's disease.

Discovered in our laboratory, activity-dependent neuroprotective protein (ADNP) interacts with key regulatory proteins, including the chromatin remodeling complex SWI/SNF, proteins associated with RNA splicing, RNA translation, microtubule dynamics, and autophagy. ADNP regulates > 400 genes during mouse embryonic development and is essential for neural tube closure. ADNP key functions extend from mice to men, with mutations causing ADNP-related ID/autism syndrome, also known as the Helsmoortel-Van der Aa syndrome. ADNP mRNA increases in lymphocytes derived from schizophrenia patients and in patients suffering from mild cognitive impairment (MCI) and further increases in Alzheimer's disease patients compared with controls. Serum ADNP levels correlate with IQ. NAP (davunetide), an ADNP snippet drug candidate, protects cognition in patients suffering from amnestic MCI preceding Alzheimer's disease and significantly enhances functional daily activities in schizophrenia patients toward future development. It is important to note that ADNP is sexually regulated in the brains of birds, mice, and men and in lymphocytes of patients suffering from schizophrenia. ADNP haploinsufficiency in mice results in significantly decreased axonal transport (with male-female differences) changes in gene expression in a sex-dependent manner, including key regulatory mechanisms during brain and heart development and function and behavioral outcomes. These findings pave the path for better understanding of brain function through the prism of sex differences.