The autism/neuroprotection-linked ADNP/NAP regulate the excitatory glutamatergic synapse
2019
Activity-dependent neuroprotective protein (ADNP), essential for brain formation, was discovered as a leading
de novo mutatedgene
causingthe
autism-like ADNP syndrome. This syndrome is phenotypically characterized by
global developmental delays, intellectual disabilities,
speech impediments, and
motor dysfunctions. The Adnp
haploinsufficientmouse mimics the human ADNP syndrome in terms of synapse density and gene expression patterns, as well as in developmental, motor, and cognitive abilities. Peripheral ADNP was also discovered as a biomarker for Alzheimer’s disease and schizophrenia, with
nasal administrationof the ADNP
snippetpeptide
NAP(enhancing endogenous ADNP activity) leading to partial cognitive and functional protection at the cellular, animal and clinical settings. Here, a novel formulation for effective delivery of
NAPis provided with superior brain penetration capabilities. Also provided are methods for treating pertinent clinical implications such as autism, cognitive impairments, olfactory deficits, and muscle strength using the formulation in the Adnp
haploinsufficientmouse. Results showed a dramatically specific increase in brain/body bioavailability with the new formulation, without breaching the blood brain barrier. Additional findings included improvements using daily intranasal treatments with
NAP, at the behavioral and brain
structural levels, diffusion tensor imaging (DTI), translatable to clinical practice. Significant effects on hippocampal and cerebral cortical expression of the presynaptic Slc17a7 gene encoding vesicular excitatory glutamate transporter 1 (VGLUT1) were observed at the RNA and immunohistochemical levels, explaining the DTI results. These findings tie for the first time a reduction in presynaptic glutamatergic synapses with the autism/Alzheimer’s/schizophrenia-linked ADNP deficiency coupled with amelioration by
NAP(CP201).
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