New horizons in schizophrenia treatment: autophagy protection is coupled with behavioral improvements in a mouse model of schizophrenia

Abstract

Autophagy plays a key role in the pathophysiology of schizophrenia as manifested by a 40% decrease in BECN1/Beclin 1 mRNA in postmortem hippocampal tissues relative to controls. This decrease was coupled with the deregulation of the essential ADNP (activity-dependent neuroprotector homeobox), a binding partner of MAP1LC3B/LC3B (microtubule-associated protein 1 light chain 3 β) another major constituent of autophagy. The drug candidate NAP (davunetide), a peptide fragment from ADNP, enhanced the ADNP-LC3B interaction. Parallel genetic studies have linked allelic variation in the gene encoding MAP6/STOP (microtubule-associated protein 6) to schizophrenia, along with altered MAP6/STOP protein expression in the schizophrenic brain and schizophrenic-like behaviors in Map6-deficient mice. In this study, for the first time, we reveal significant decreases in hippocampal Becn1 mRNA and reversal by NAP but not by the antipsychotic clozapine (CLZ) in Map6-deficient (Map6(+/-)) mice. Normalization of Becn1 expression by NAP was coupled with behavioral protection against hyperlocomotion and cognitive deficits measured in the object recognition test. CLZ reduced hyperlocomotion below control levels and did not significantly affect object recognition. The combination of CLZ and NAP resulted in normalized outcome behaviors. Phase II clinical studies have shown NAP-dependent augmentation of functional activities of daily living coupled with brain protection. The current studies provide a new mechanistic pathway and a novel avenue for drug development.

Autophagy and Schizophrenia: A Closer Look at How Dysregulation of Neuronal Cell Homeostasis Influences the Pathogenesis of Schizophrenia

“…Administration of NAP, a peptide fragment of ADNP also known as davunetide, enhanced the ADNP-LC3 interaction and reversed the decrease in hippocampal BECN1 mRNA levels in a mouse model of schizophrenia (MAP6-deficiency) (Merenlender-Wagner et al, 2014). Normalization of BECN1 expression by NAP led to positive outcomes in the behavioral phenotype of MAP6-deficient mice.…”

“…The changes observed in treated animals included decreased hyper-locomotion and cognitive deficits as measured by the object recognition test. The combination of NAP with clozapine, an FDA-approved antipsychotic used in refractory schizophrenia, resulted in complete normalization of behavioral outcomes (Merenlender-Wagner et al, 2014). These studies highlight a potential role for NAP-mediated autophagy rescue in mouse models of schizophrenia and suggest a new therapeutic strategy of supplying adjuvant treatment along with antipsychotic medication to bolster the efficacy of therapy.…”

Microbiota changes associated with ADNP deficiencies: rapid indicators for NAP (CP201) treatment of the ADNP syndrome and beyond

“…Regarding schizophrenia, we showed that ADNP is linked with the regulation of autophagy, and we further showed that this process is disrupted in schizophrenia and corrected by NAP treatment (Merenlender-Wagner et al 2014, 2015. In this respect, an impaired gut microbiome inhibits the autophagy-mediated protein clearance process and a distinct gut microbiome composition can change the neurotransmitter levels in the brain through the vagal afferent fibers also pertinent for AD (Bostanciklioglu 2019).…”

Clozapine Modulates Glucosylceramide, Clears Aggregated Proteins, and Enhances ATG8/LC3 in Caenorhabditis elegans

“…Administration of NAP, a peptide fragment of ADNP, enhances the activity of ADNP-LC3, a key component of the autophagic machinery interaction and reverses the decrease in hippocampal BECN1 mRNA levels in a mouse model of schizophrenia. The combination of NAP with clozapine results in complete normalization of behavioral outcomes (Merenlender-Wagner et al, 2014).…”