Activity-Dependent Neuroprotective Protein Snippet NAP Reduces Tau Hyperphosphorylation and Enhances Learning in a Novel Transgenic Mouse Model

Laboratory of Experimental Pedagogy, Aristotle University of Thessaloniki, Saloníki, Central Macedonia, Greece
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.97). 12/2007; 323(2):438-49. DOI: 10.1124/jpet.107.129551
Source: PubMed


Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate essential genes. Because complete ADNP deficiency is embryonic lethal, the outcome of partial ADNP deficiency was examined. ADNP(+/-) mice exhibited cognitive deficits, significant increases in phosphorylated tau, tangle-like structures, and neurodegeneration compared with ADNP(+/+) mice. Increased tau hyperphosphorylation is known to cause memory impairments in neurodegenerative diseases associated with tauopathies, including the most prevalent Alzheimer's disease. The current results suggest that ADNP is an essential protein for brain function and plays a role in normal cognitive performance. ADNP-deficient mice offer an ideal paradigm for evaluation of cognitive enhancers. NAP (NAPVSIPQ) is a peptide derived from ADNP that interacts with microtubules and provides potent neuroprotection. NAP treatment partially ameliorated cognitive deficits and reduced tau hyperphosphorylation in the ADNP(+/-) mice. NAP is currently in phase II clinical trials assessing effects on mild cognitive impairment.

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    • "As recently discovered, ADNP binds eukaryotic initiation factor 4E (eIF4E) and regulates its expression in a sex-dependent manner , with eIF4E being a protein translation factor associated with autism [11] [29]. While complete Adnp knockout was found to be lethal [37], Adnp +/− mice develop cognitive and social behavior deficits [43]. This mouse model is of dual importance, exhibiting both Alzheimer's disease related symptoms, as well as autistic-like characteristics [29]. "
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    ABSTRACT: ADNP is a protein necessary for brain development, important for brain plasticity, cognitive and social functioning, characteristics that are all impaired in autism and in the Adnp(+/-) mouse model, in a sex-dependent manner. ADNP was originally discovered as a protein that is secreted from glial cells in response to vasoactive intestinal peptide (VIP). VIP is a major neuroprotective peptide in the CNS and PNS and was also associated with social recognition in rodents and aggression, pair-bonding and parental behaviors in birds. Comparative sequence alignment revealed high evolutionary conservation of ADNP in Chordata. Despite its importance in brain function, ADNP has never been studied in birds. Zebra finches (Taeniopygia guttata) are highly social songbirds that have a sexually-dichotomous anatomical brain structure, with males demonstrating a developed song system, presenting a model to study behavior and potential sexually-dependent fundamental differences. Here, using quantitative real time polymerase chain reaction (qRT-PCR), we discovered sexually-dichotomous and age related differences in ADNP mRNA expression in three different regions of the song bird brain-cerebellum, cerebrum, and brain stem. Higher levels of ADNP mRNA were specifically found in young male compared to the female cerebrum, while aging caused a significant 2 and 3-fold decrease in the female and male cerebrum, respectively. Furthermore, a comparison between the three tested brain regions revealed unique sex-dependent ADNP mRNA distribution patterns, affected by aging. Future studies are aimed at deciphering the function of ADNP in birds, toward a better molecular understanding of sexual dichotomy in singing behavior in birds. Copyright © 2015. Published by Elsevier Inc.
    Peptides 04/2015; DOI:10.1016/j.peptides.2015.04.008 · 2.62 Impact Factor
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    • "Alzheimer's diseases (AD) and Amyloid lateral sclerosis (ALS), mechanism of protection by NAP was mediated through prevention of hyper phosphorylation of tau protein and thereby increasing the micro-tubular movements [30]. Mechanism of neuronal damage in hypoxia is not well understood, yet oxidative stress due to elevated reactive oxygen species is proposed as one of the leading cause for the progression of pathologies in hypoxia associated diseases like high altitude cerebral oedema (HACE), Previous studies have also suggested the prophylactic role of NAP in hypobaric hypoxia in rat model, with concomitant reduction in reactive oxygen species [24]. "
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    ABSTRACT: Hypoxia is a well-known threat to neuronal cells and triggers the pathophysiological syndromes in extreme environments such as high altitudes and traumatic conditions such as stroke. Among several prophylactic molecules proven suitable for ameliorating free radical damage, NAP (an octapeptide with initial amino acids: asparagine/N, alanine/A, and proline/P) can be considered superlative, primarily due to its high permeability into brain through blood-brain barrier and observed activity at femtomolar concentrations. Several mechanisms of action of NAP have been hypothesized for its protective role during hypoxia, yet any distinct mechanism is unknown. Oxidative stress is advocated as the leading event in hypoxia; we, therefore, investigated the regulation of key antioxidant genes to understand the regulatory role of NAP in providing neuroprotection. Primary neuronal culture of rat was subjected to cellular hypoxia by limiting the oxygen concentration to 0.5% for 72 h and observing the prophylactic efficacies of 15fM NAP by conventional cell death assays using flow cytometry. We performed real-time quantitative polymerase chain reaction to comprehend the regulatory mechanism. Further, we validated the significantly regulated candidates by enzyme assays and immunoblotting. In the present study, we report that NAP regulates a major clad of cellular antioxidants and there is an involvement of more than one route of action in neuroprotection during hypoxia.
    Free Radical Research 03/2015; DOI:10.3109/10715762.2015.1011153 · 2.98 Impact Factor
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    • "We have previously observed (Fleming et al. 2011) beneficial effects in the Thy1-aSyn mouse model overexpressing a-syuclein of intranasal administration of NAP (NAPVSIPQ; davunetide or AL-108), a neuroprotective peptide derived from activity-dependent neuroprotective protein (ADNP; Bassan et al. 1999) which stabilizes microtubules and decreases tau hyperphosphorylation (Matsuoka et al. 2007, 2008; Vulih-Shultzman et al. 2007; Shiryaev et al. 2009; Jouroukhin et al. 2012, 2013). In our previous pilot study, 2 lg/mouse NAP given daily for 8 weeks to Thy1-aSyn mice improved motor coordination deficits and a-synuclein pathology in the substantia nigra (SN) (Fleming et al. 2011). "
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    ABSTRACT: Genome-wide association studies have identified strong associations between the risk of developing Parkinson's disease (PD) and polymorphisms in the genes encoding α-synuclein and the microtubule-associated protein tau. However, the contribution of tau and its phosphorylated form (p-tau) to α-synuclein-induced pathology and neuronal dysfunction remains controversial. We have assessed the effects of NAP (davunetide), an eight-amino acid peptide that decreases tau hyperphosphorylation, in mice overexpressing wild-type human α-synuclein (Thy1-aSyn mice), a model that recapitulates aspects of PD. We found that the p-tau/tau level increased in a subcortical tissue block that includes the striatum and brain stem, and in the cerebellum of the Thy1-aSyn mice compared to nontransgenic controls. Intermittent intranasal NAP administration at 2 μg/mouse per day, 5 days a week, for 24 weeks, starting at 4 weeks of age, significantly decreased the ratio of p-tau/tau levels in the subcortical region while a higher dose of 15 μg/mouse per day induced a decrease in p-tau/tau levels in the cerebellum. Both NAP doses reduced hyperactivity, improved habituation to a novel environment, and reduced olfactory deficits in the Thy1-aSyn mice, but neither dose improved the severe deficits of motor coordination observed on the challenging beam and pole, contrasting with previous data obtained with continuous daily administration of the drug. The data reveal novel effects of NAP on brain p-tau/tau and behavioral outcomes in this model of synucleinopathy and suggest that sustained exposure to NAP may be necessary for maximal benefits.
    10/2014; 2(5). DOI:10.1002/prp2.65
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