Literature Search Results for Gene ADNP

1Peptides 2010 Jul 31: 1368-73
PMID20417241
TitleNAP (davunetide) enhances cognitive behavior in the STOP heterozygous mouse--a microtubule-deficient model of schizophrenia.
AbstractNAP (generic name, davunetide) is an active fragment of activity-dependent neuroprotective protein (ADNP). ADNP-/- embryos exhibit CNS dysgenesis and die in utero. ADNP+/- mice survive but demonstrate cognitive dysfunction coupled with microtubule pathology. NAP treatment ameliorates, in part, ADNP-associated dysfunctions. The microtubule, stable tubule-only polypeptide (STOP) knockout mice were shown to provide a reliable model for schizophrenia. Here, STOP-/- as well as STOP+/- showed schizophrenia-like symptoms (hyperactivity) that were ameliorated by chronic treatment with the antipsychotic drug, clozapine. Daily intranasal NAP treatment significantly decreased hyperactivity in the STOP+/- mice and protected visual memory.
SCZ Keywordsschizophrenia, schizophrenic
2Peptides 2011 Feb 32: 428-31
PMID21050875
TitleMicrotubules, schizophrenia and cognitive behavior: preclinical development of davunetide (NAP) as a peptide-drug candidate.
AbstractNAP (davunetide) is an active fragment of activity-dependent neuroprotective protein (ADNP). ADNP and the homologous protein ADNP2 provide cell protection. ADNP is essential for brain formation, proper development and neuronal plasticity, all reported to be impaired in schizophrenia. ADNP haploinsufficiecy inhibits social and cognitive functions, major hallmarks in schizophrenia. Imbalance in ADNP/ADNP2 expression in the schizophrenia brain may impact disease progression. NAP treatment partly ameliorates ADNP haploinsufficiecy. The microtubule, stable tubule-only polypeptide (STOP)-deficient mice were shown to provide a reliable model for schizophrenia. Daily intranasal NAP treatment significantly decreased hyperactivity in STOP-deficient mice and protected visual memory, supporting further clinical development.
SCZ Keywordsschizophrenia, schizophrenic
3Eur Neuropsychopharmacol 2011 May 21: 355-61
PMID20598862
TitleActivity-dependent neuroprotective protein (ADNP) expression level is correlated with the expression of the sister protein ADNP2: deregulation in schizophrenia.
AbstractActivity-dependent neuroprotective protein (ADNP) and the homologous protein ADNP2 provide cell protection. ADNP is essential for brain formation, proper brain development and neuronal plasticity, all reported to be impaired in the schizophrenia patient brains. Furthermore, reduction in ADNP expression affects social interactions, a major hallmark of schizophrenia. To evaluate a possible involvement of ADNP and ADNP2 in the pathophysiology of schizophrenia in humans, we measured relative brain mRNA transcripts of both proteins compared with control subjects. Quantitative real time polymerase chain reaction in postmortem hippocampal specimens from normal control subjects exhibited a significant ADNP to ADNP2 transcript level correlation (r=0.931, p<0.001), also apparent in a neuroglial model system. In contrast, in the hippocampus of matched schizophrenia patients, this correlation (r=0.637, p=0.014) was drastically decreased in a statistically significant manner (p=0.03), mirroring disease-associated increased ADNP2 transcripts. In the prefrontal cortex of schizophrenia patients the correlation between ADNP and ADNP2 mRNA levels was apparently higher than in the hippocampus (r=0.854, p<0.001), but did not reach a significant difference (p=0.25). Thus, imbalance in ADNP/ADNP2 expression in the brain may impact disease progression in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
4Curr. Pharm. Des. 2011 -1 17: 1040-4
PMID21524250
TitleNAP (davunetide) provides functional and structural neuroprotection.
AbstractNAP (davunetide) is an eight amino acid peptide (NAPVSIPQ) that has been shown to provide potent neuroprotection, in vitro and in vivo. In human clinical trials, NAP has been shown to increase memory scores in patients suffering from amnestic mild cognitive impairment, a precursor to Alzheimer's disease and to enhance functional daily behaviors in schizophrenia patients. NAP is derived from activity-dependent neuroprotective protein (ADNP) a molecule that is essential for brain formation, interacting with chromatin associated protein alpha and the chromatin remodeling complex SWI/SNF and regulating >400 genes during embryonic development. Partial loss in ADNP results in cognitive deficits and pathology of the microtubule associated protein tau (tauopathy) that is ameliorated in part by NAP replacement therapy. Recent studies increased the scope of NAP neuroprotection and provided further insights into the NAP mechanisms of action. Thus, it has been hypothesized that the presence of tau on axonal microtubules renders them notably less sensitive to the microtubule-severing protein katanin, and NAP was shown to protect microtubules from katanin disruption in the face of reduced tau expression. Parallel studies showed that NAP reduced the number of apoptotic neurons through activation of PI-3K/Akt pathway in the cortical plate or both PI-3K/Akt and MAPK/MEK1 kinases in the white matter. The interaction of these disparate yet complementary pathways is the subject of future studies toward human brain neuroprotection in the clinical scenario.
SCZ Keywordsschizophrenia, schizophrenic
5Prog. Neuropsychopharmacol. Biol. Psychiatry 2013 Oct -1: -1
PMID24513021
TitleIncreased Stability of Microtubules in Cultured Olfactory Neuroepithelial Cells from Individuals with Schizophrenia.
AbstractMicrotubules (MTs) are essential components of the cytoskeleton that play critical roles in neurodevelopment and adaptive central nervous system functioning. MTs are essential to growth cone advance and ultrastructural events integral to synaptic plasticity; these functions figure significantly into current pathophysiologic conceptualizations of schizophrenia. To date, no study has directly investigated MT dynamics in humans with schizophrenia. We therefore compared the stability of MTs in olfactory neuroepithelial (OE) cells between schizophrenia cases and matched nonpsychiatric comparison subjects. For this purpose, we applied nocodazole (Nz) to cultured OE cells obtained from tissue biopsies from seven living schizophrenia patients and seven matched comparison subjects; all schizophrenia cases were on antipsychotic medications. Nz allows MT depolymerization to be followed but prevents repolymerization, so that in living cells treated for varying time intervals, the MTs that are stable for a given treatment interval remain. Our readout of MT stability was the time at which fewer than 10 MTs per cell could be distinguished by anti-?-tubulin immunofluorescence. The percentage of cells with >10 intact MTs at specified intervals following Nz treatment was estimated by systematic uniform random sampling with Visiopharm software. These analyses showed that the mean percentages of OE cells with intact MTs were significantly greater for schizophrenia cases than for the matched comparison subjects at 10, 15, and 30minutes following Nz treatment indicating increased MT stability in OE cells from schizophrenia patients (p=.0007 at 10minutes; p=.0008 at 15minutes; p=.036 at 30minutes). In conclusion, we have demonstrated increased MT stability in nearly all cultures of OE cells from individuals with schizophrenia who received several antipsychotic treatments, versus comparison subjects matched for age and sex. While we cannot rule out a possible confounding effect of antipsychotic medications, these findings may reflect analogous neurobiological events in at least a subset of immature neurons or other cell types during gestation, or newly generated cells destined for the olfactory bulb or hippocampus, suggesting a mechanism that underlies findings of postmortem and neuroimaging investigations of schizophrenia. Future studies aimed at replicating these findings, including samples of medication-naïve subjects with schizophrenia, and reconciling the results with other studies, will be necessary. Although the observed abnormalities may suggest one of a number of putative pathophysiologic anomalies in schizophrenia, this work may ultimately have implications for an improved understanding of pathogenic processes related to this disorder.
SCZ Keywordsschizophrenia, schizophrenic
6Autophagy 2014 -1 10: 2324-32
PMID25484074
TitleNew horizons in schizophrenia treatment: autophagy protection is coupled with behavioral improvements in a mouse model of schizophrenia.
AbstractAutophagy 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 ?) 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.
SCZ Keywordsschizophrenia, schizophrenic
7Autophagy 2014 -1 10: 2324-32
PMID25484074
TitleNew horizons in schizophrenia treatment: autophagy protection is coupled with behavioral improvements in a mouse model of schizophrenia.
AbstractAutophagy 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 ?) 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.
SCZ Keywordsschizophrenia, schizophrenic
8Mol. Psychiatry 2014 Oct 19: 1115-24
PMID25178163
TitleThe NAP motif of activity-dependent neuroprotective protein (ADNP) regulates dendritic spines through microtubule end binding proteins.
AbstractThe NAP motif of activity-dependent neuroprotective protein (ADNP) enhanced memory scores in patients suffering from mild cognitive impairment and protected activities of daily living in schizophrenia patients, while fortifying microtubule (MT)-dependent axonal transport, in mice and flies. The question is how does NAP fortify MTs? Our sequence analysis identified the MT end-binding protein (EB1)-interacting motif SxIP (SIP, Ser-Ile-Pro) in ADNP/NAP and showed specific SxIP binding sites in all members of the EB protein family (EB1-3). Others found that EB1 enhancement of neurite outgrowth is attenuated by EB2, while EB3 interacts with postsynaptic density protein 95 (PSD-95) to modulate dendritic plasticity. Here, NAP increased PSD-95 expression in dendritic spines, which was inhibited by EB3 silencing. EB1 or EB3, but not EB2 silencing inhibited NAP-mediated cell protection, which reflected NAP binding specificity. NAPVSKIPQ (SxIP=SKIP), but not NAPVAAAAQ mimicked NAP activity. ADNP, essential for neuronal differentiation and brain formation in mouse, a member of the SWI/SNF chromatin remodeling complex and a major protein mutated in autism and deregulated in schizophrenia in men, showed similar EB interactions, which were enhanced by NAP treatment. The newly identified shared MT target of NAP/ADNP is directly implicated in synaptic plasticity, explaining the breadth and efficiency of neuroprotective/neurotrophic capacities.
SCZ Keywordsschizophrenia, schizophrenic
9J. Mol. Neurosci. 2014 Jan 52: 1-9
PMID24458740
TitleNAP alpha-aminoisobutyric acid (IsoNAP).
AbstractWe 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 ?-sheet breaker characteristics, thereby reducing protein misfolding. Three lines of investigations were chosen: (1) protection against the AD-associated amyloid ? (1-42), A?1-42, 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 A?1-42-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.
SCZ Keywordsschizophrenia, schizophrenic
10Mol. Psychiatry 2015 Feb 20: 126-32
PMID24365867
TitleAutophagy has a key role in the pathophysiology of schizophrenia.
AbstractAutophagy is a process preserving the balance between synthesis, degradation and recycling of cellular components and is therefore essential for neuronal survival and function. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3). Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This is in contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which we have previously found to be deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients, similar to increases in the anti-apoptotic, beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial stages of the disease, possibly reflecting a compensatory effect. The increase in ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected to clozapine treatment. ADNP haploinsufficiency in mice, which results in age-related neuronal death, cognitive and social dysfunction, exhibited reduced hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.
SCZ Keywordsschizophrenia, schizophrenic
11Sci Rep 2015 -1 5: 16300
PMID26553741
TitleRisperidone and NAP protect cognition and normalize gene expression in a schizophrenia mouse model.
AbstractMutated disrupted in schizophrenia 1 (DISC1), a microtubule regulating protein, leads to schizophrenia and other psychiatric illnesses. It is hypothesized that microtubule stabilization may provide neuroprotection in schizophrenia. The NAP (NAPVSIPQ) sequence of activity-dependent neuroprotective protein (ADNP) contains the SxIP motif, microtubule end binding (EB) protein target, which is critical for microtubule dynamics leading to synaptic plasticity and neuroprotection. Bioinformatics prediction for FDA approved drugs mimicking SxIP-like motif which displace NAP-EB binding identified Risperidone. Risperidone or NAP effectively ameliorated object recognition deficits in the mutated DISC1 mouse model. NAP but not Risperidone, reduced anxiety in the mutated mice. Doxycycline, which blocked the expression of the mutated DISC1, did not reverse the phenotype. Transcripts of Forkhead-BOX P2 (Foxp2), a gene regulating DISC1 and associated with human ability to acquire a spoken language, were increased in the hippocampus of the DISC1 mutated mice and were significantly lowered after treatment with NAP, Risperidone, or the combination of both. Thus, the combination of NAP and standard of care Risperidone in humans may protect against language disturbances associated with negative and cognitive impairments in schizophrenia.
SCZ Keywordsschizophrenia, schizophrenic
12Front Aging Neurosci 2015 -1 7: 205
PMID26578950
TitleADNP: in search for molecular mechanisms and innovative therapeutic strategies for frontotemporal degeneration.
AbstractActivity-dependent neuroprotective protein (ADNP) is deregulated in Alzheimer's disease (AD) and in schizophrenia and mutated in autism. In mice, ADNP is essential for brain formation and ADNP haploinsufficiency is associated with cognitive and social deficits and tauopathy. Tauopathy, a major pathology in AD, is also found in ~45% of frontotemporal dementias (FTDs). Tau transcript, a product of a single gene, undergoes alternative splicing. Tau splicing seems to be altered in FTD brain. In transgenic mice overexpressing a mutated tau in the cerebral cortex, significant increases in ADNP transcript expression were observed in the cerebral cortex of young transgenic mice (~disease onset) and a marked decrease with aging as compared to control littermates. ADNP is a member of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex also associated with alternative splicing, including tau transcript splicing. Further cellular interactions of ADNP include association with microtubules, with tau being a microtubule-associated protein. NAP (davundetide), a novel drug candidate derived from ADNP, increases ADNP-microtubule association and protects against tauopathy and cognitive deficiencies in mice. Although, NAP did not provide protection in progressive supranuclear palsy (PSP), a pure tauopathy, it increased cognitive scores in amnestic mild cognitively impaired patients and protected functional activity in schizophrenia patients. This mini-review focuses on ADNP in the context of FTD and tau/microtubules and proposes NAP as a novel drug target for future clinical evaluations.
SCZ Keywordsschizophrenia, schizophrenic
13J. Alzheimers Dis. 2015 -1 45: 57-73
PMID25428252
TitleActivity-dependent neuroprotective protein (ADNP): a case study for highly conserved chordata-specific genes shaping the brain and mutated in cancer.
AbstractThe recent finding of activity-dependent neuroprotective protein (ADNP) as a protein decreased in serum of patients with Alzheimer's disease (AD) compared to controls, alongside with the discovery of ADNP mutations in autism and coupled with the original description of cancer mutations, ignited an interest for a comparative analysis of ADNP with other AD/autism/cancer-associated genes. We strive toward a better understanding of the molecular structure of key players in psychiatric/neurodegenerative diseases including autism, schizophrenia, and AD. This article includes data mining and bioinformatics analysis on the ADNP gene and protein, in addition to other related genes, with emphasis on recent literature. ADNP is discovered here as unique to chordata with specific autism mutations different from cancer-associated mutation. Furthermore, ADNP exhibits similarities to other cancer/autism-associated genes. We suggest that key genes, which shape and maintain our brain and are prone to mutations, are by in large unique to chordata. Furthermore, these brain-controlling genes, like ADNP, are linked to cell growth and differentiation, and under different stress conditions may mutate or exhibit expression changes leading to cancer propagation. Better understanding of these genes could lead to better therapeutics.
SCZ Keywordsschizophrenia, schizophrenic