Δημοσίευση

The autism/neuroprotection-linked ADNP/NAP regulate the excitatory glutamatergic synapse.

ΤίτλοςThe autism/neuroprotection-linked ADNP/NAP regulate the excitatory glutamatergic synapse.
Publication TypeJournal Article
Year of Publication2019
AuthorsSragovich, S., Malishkevich A., Piontkewitz Y., Giladi E., Touloumi O., Lagoudaki R., Grigoriadis N., & Gozes I.
JournalTransl Psychiatry
Volume9
Issue1
Pagination2
Date Published2019 01 15
ISSN2158-3188
Abstract

Activity-dependent neuroprotective protein (ADNP), essential for brain formation, was discovered as a leading de novo mutated gene causing the autism-like ADNP syndrome. This syndrome is phenotypically characterized by global developmental delays, intellectual disabilities, speech impediments, and motor dysfunctions. The Adnp haploinsufficient mouse 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 administration of the ADNP snippet peptide 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 NAP is 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 haploinsufficient mouse. 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).

DOI10.1038/s41398-018-0357-6
Alternate JournalTransl Psychiatry
PubMed ID30664622
PubMed Central IDPMC6341082

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