NAP alpha-aminoisobutyric acid (IsoNAP)
| Autor: | Merav David, Illana Gozes, Anat Idan-Feldman, Yulie Schirer, Sharon Furman-Assaf |
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| Rok vydání: | 2014 |
| Předmět: |
Aminoisobutyric Acids
Population Peptide Nerve Tissue Proteins tau Proteins Pharmacology Neuroprotection Cellular and Molecular Neuroscience Mice mental disorders medicine Animals education Maze Learning Cells Cultured chemistry.chemical_classification Cerebral Cortex Homeodomain Proteins Neurons education.field_of_study Amyloid beta-Peptides Chemistry Neurodegeneration General Medicine medicine.disease In vitro Peptide Fragments Rats Nap Neuroprotective Agents Biochemistry Astrocytes Toxicity Tauopathy Oligopeptides |
| Zdroj: | Journal of molecular neuroscience : MN. 52(1) |
| ISSN: | 1559-1166 |
| Popis: | We set out to identify NAP (davunetide) analogs, providing neuroprotection and reducing tau pathology, specifically addressing protection against protein misfolding. NAP (NAPVSIPQ, intranasal formulation AL-108) is a drug candidate that (1) had a statistically significant impact on two measures, namely digit span and delayed-match-to-sample, tests of verbal recall and visual working memory, respectively, in patient population of mild cognitive impairment [preceding Alzheimer’s disease (AD)] and (2) protected functional activities of daily living in schizophrenia patients. Previous preclinical studies have shown that stabilization of NAP by replacement of all l-amino acids by d-amino acids resulted in an active peptide, d-NAP. Other NAP mimetics are now explored. A new NAP analog was designed that included replacement of the proline residues by alpha-aminoisobutyric acid to enhance β-sheet breaker characteristics, thereby reducing protein misfolding. Three lines of investigations were chosen: (1) protection against the AD-associated amyloid β (1-42), Aβ1-42, peptide toxicity in cell cultures; (2) inhibition of AD-associated tau aggregation in vitro; and (3) cognitive protection in a mouse model of deficiencies of the NAP parent protein, activity-dependent neuroprotective protein (ADNP), exhibiting tau pathology and neurodegeneration. NAP alpha-aminoisobutyric acid (IsoNAP) protected neurons against AD-associated Aβ1-42-toxicity, inhibited the aggregation of the tau-derived peptide VQIVYK (important for the aggregation of tau into paired helical filaments, which form the tangles found in AD and related disorders), and protected cognitive functions in a model of ADNP deficiency. With AD being the major tauopathy, novel NAP derivatives that reduce tauopathy and provide neuroprotection as well as cognitive protection are of scientific and clinical interest. |
| Databáze: | OpenAIRE |
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