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INTRODUCTION Baseline and longitudinal characteristics of cerebrospinal fluid (CSF) growth‐associated protein 43 (GAP‐43) and plasma neurofilament light (NfL) and how they correlate interactively with neurodegeneration and cognitive decline in Alzheimer's disease (AD) are not fully understood. METHODS We investigated dynamic changes of CSF GAP‐43 and plasma NfL across different AD stages and their association with longitudinal neurodegeneration and cognitive decline up to 12 years. RESULTS Individuals with hippocampal atrophy, AD‐signature cortical thinning, or hypometabolism (N+) had faster plasma NfL increase rates than healthy individuals, regardless of amyloid/tau status. In contrast, none of these N+ imaging indicators correlated with more rapid increases in CSF GAP‐43. Furthermore, CSF GAP‐43 and plasma NfL synergistically predicted subsequent gray matter atrophy, cortical thinning, hypometabolism of the middle temporal region, and cognition. DISCUSSION CSF GAP‐43‐associated presynaptic loss indicates tau‐dependent early neurodegeneration, whereas the axonal degeneration indicated by plasma NfL is a relatively late atrophy/hypometabolism‐associated fluid neurodegeneration biomarker. Highlights Plasma neurofilament light (NfL) was increased in N+ or cognitively impaired individuals. Increases in tau‐dependent cerebrospinal fluid CSF growth‐associated protein 43 (GAP‐43) before imaging neurodegeneration indicators. CSF GAP‐43 and plasma NfL are synergistically related to longitudinal neurodegeneration. CSF GAP‐43 and plasma NfL are synergistically related to longitudinal cognitive decline.

Objective Prenatal stress (PS) is a problematic situation resulting in psychological implications such as social anxiety. Ubiquitous extremely low‐frequency electromagnetic fields (ELF‐EMF) have been confirmed as a potential physiological stressor; however, useful neuroregenerative effect of these types of electromagnetic fields has also frequently been reported. The aim of the present study was to survey the interaction of PS and ELF‐EMF on anxiety‐like behavior. Method A total of 24 female rats 40 days of age were distributed into four groups of 6 rats each: control, stress (their mothers were exposed to stress), EMF (their mothers underwent to ELF‐EMF), and EMF/stress (their mothers concurrently underwent to stress and ELF‐EMF). The rats were assayed using elevated plus‐maze and open field tests. Results Expressions of the hippocampus GAP‐43, BDNF, and caspase‐3 (cas‐3) were detected by immunohistochemistry in Cornu Ammonis 1 (CA1) and dentate gyrus (DG) of the hippocampus and prefrontal cortex (PFC). Anxiety‐like behavior increased in all treatment groups. Rats in the EMF/stress group presented more serious anxiety‐like behavior. In all treatment groups, upregulated expression of cas‐3 was seen in PFC, DG, and CA1 and downregulated expression of BDNF and GAP‐43 was seen in PFC and DG and the CA1. Histomorphological study showed vast neurodegenerative changes in the hippocampus and PFC. Conclusion The results showed ,female rats that underwent PS or/and EMF exhibited critical anxiety‐like behavior and this process may be attributed to neurodegeneration in PFC and DG of the hippocampus and possibly decreased synaptic plasticity so‐called areas. The present study showed that PS and ELF‐EMF could have potential hazardous implications in neurogenration in hippocamus and PFC in the pregnancy period and could result in anxiety‐like behavior in offspring. We also found for the first time that omnipresent ELF‐EMF not only induces neurodegeneration effects on hippocamus and PFC but also could exacerbate anxiey like behavior of PS, which may be attributed to hippocampal and PFC neurodegeneration and also neuroplasticity reduction.

Background: GAP43, a membrane phosphoprotein with high expression level in the developing brains, plays an important role in higher integrative functions of the brain. Materials and Methods: To explore the association of GAP43 with schizophrenia, 11 single-nucleotide polymorphisms (SNPs) were examined in a Northeast Chinese Han sample set consisting of 741 schizophrenia patients and 1330 healthy controls. Results: The results showed that three SNPs were associated with schizophrenia (rs2028248, rs6790048, and rs2164930). Haplotype analysis also revealed a significant association of a strong linkage disequilibrium block (rs2164930-rs11926976-rs16823991) with schizophrenia. Conclusion: The current findings suggested that the human GAP43 gene may be a susceptibility gene for schizophrenia.

Nerve regeneration during healing of Achilles tendon rupture in the rat was studied by immunohistochemistry including semi-quantitative assessment. Neuronal markers for regenerating and mature fibers, ie., growth associated protein 43 (GAP-43) and protein gene product 9.5 (PGP 9.5), respectively, were analyzed at different time points (1–16 weeks) post-rupture. In the paratenon, both the ruptured and intact contralateral tendon (control) consistently exhibited immunoreactivity to the two neuronal markers. However, in the proper tendinous tissue only the ruptured tendon showed immunoreactivity to GAP-43 and PGP 9.5. This expression was seen already at week 1 post-rupture to reach a peak at week 6 followed by a successive drop till week 16. Also the occurrence of sensory and autonomic fibers according to immunoreactivity for calcitonin gene-related peptide (CGRP) and neuropeptide Y (NPY), respectively, was analyzed. CGRP-positivity was abundantly seen from weeks 2–6 in both perivascular and sprouting free nerve endings in the proper tendon tissue undergoing healing. NPY appeared later, at weeks 6–8 post-rupture around blood vessels mainly located in the surrounding loose connective tissue. Apart from a role in vasoaction (CGRP, vasodilatory; NPY, vasoconstrictory), both neuropeptides have been implicated in fibroblast and endothelial cell proliferation required for angiogenesis. The present study shows that early healing of ruptured tendons is characterized by an orchestrated, temporal appearance of nerve fibers expressing peptides with different actions. The observed pattern of neuronal regeneration and neuropeptide expression may prove to be important for normal connective tissue healing.

Purpose: Botulinum toxin A (BoNT-A) is used to manage spasticity in cerebral palsy. BoNT-A cleaves SNAP-25 protein, blocking acetylcholine release and weakening the muscle. Nicotinic acetylcholine receptors (nAChR) including alpha, beta, delta, gamma, and epsilon subunits, and GAP-43 protein are associated with functional recovery of neuromuscular junctions (NMJ) following BoNT-A. To better understand the mechanism behind this functional recovery, this study attempted to (1) document changes in NMJ morphometry following BoNT-A, and (2) determine the gene expression of nAChR subunits, SNAP-25, and GAP-43 protein. Methods: In this rat study (46 rats), 6 units/kg body weight of BoNT-A was injected into the gastrocnimus. NMJ morphometry and the time course of gene expression of nAChR subunits, SNAP-25, and GAP-43 were evaluated up to 1 year post-injection. Results: NMJ morphometry: gutter depth was reduced vs. the control side at two months, and normalizing by 6 months following BoNT. nAChR alpha mRNA and gamma mRNA increased by 3 days, peaked at 7 days and returned to control levels; delta mRNA peaked at 3 days. Epsilon mRNA peaked by 7 days. SNAP-25 mRNA increased from 60 to 90 days, returning to control levels by 6 months. GAP-43 mRNA was unchanged. Conclusions: Specific nAChR subunit mRNA expression up-regulates and then returns to normal within two weeks, preceding changes in NMJ morphometry. Although GAP-43 participates in nerve sprouting, no increase of GAP-43 mRNA occurred following BoNT-A. Delayed up-regulation of SNAP-25 mRNA might be associated with muscle functional recovery.

Aim: Extract of Hominis Placenta (HP) has been used in oriental medicine as an agent for improving physiological function. The present study was conducted to investigate whether HP treatment in an experimental sciatic nerve injury animal model produces growth‐promoting effects on regenerating peripheral nerve fibers after injury. Methods: After HP was injected into a sciatic nerve injury site, changes in protein levels were analyzed in the regenerating nerve area by Western blotting and immunofluorescence staining analyses. For quantitative assessment of axonal regeneration, a retrograde tracing technique was used to identify the neuronal cell bodies corresponding to regenerating axons, and the extent of neurite outgrowth in cultured dorsal root ganglia (DRG) sensory neurons prepared from animals that had experienced a sciatic nerve crush injury 7 d before neuron collection was analyzed. Results: Induction levels of axonal growth‐associated protein (GAP‐43) in the injured sciatic nerves were elevated by HP treatment. HP treatment also upregulated cell division cycle 2 (Cdc2) protein levels in the distal stump of the injured sciatic nerve. Induced Cdc2 protein was detected in Schwann cells, suggesting that Cdc2 kinase activity maybe involved in the growth‐promoting activity of regenerating axons via Schwann cell proliferation. Cell body measurement by retrograde tracing indicated that HP treatment produced significant increases in regenerating motor axons. Finally, HP treatment of cultured DRG sensory neurons significantly increased neurite arborization and elongation. Conclusion: HP promotes the regeneration of injured sciatic axons by upregulating the synthesis of regeneration‐related protein factors such as GAP‐43 and Cdc2.

We have analysed differential gene expression in v-jun-transformed chicken embryo fibroblasts (CEF) compared to normal CEF by using the directional tag PCR subtraction method. From a first generation of putative Jun targets four clones were selected for study; they are upregulated in jun-transformed cells. Three of these clones showed homology to known genes: glutaredoxin, growth associated protein (GAP)-43/neuromodulin, and phenobarbital-induced cytochrome P450. The expression of these genes was analysed in fibroblasts transformed by various oncogenes. Expression of the glutaredoxin mRNA could be induced by a Jun-estrogen receptor chimaera in the absence of de novo protein biosynthesis. Based on this observation we conclude that glutaredoxin is a direct target of v-Jun.

Cisplatin is a standard first-line chemotherapeutic agents for treating advanced non-small cell lung cancer. Unfortunately, the clinical application cisplatin is restricted because it induces serious adverse reaction. The aim of this study is to investigate the influence and probable mechanism of berberine on cisplatin antineoplastic effect on lung cancer A549 cells. The total Cx43 protein amount, localization of Cx43 on cell membrane, and gap junction function were observed after the A549 cells were treated with berberine. The influence of berberine on the antitumor action of cisplatin was detected by standard colony-forming assay. Protein kinase C (PKC) protein, which regulates the gap junction, was subsequently determined. Berberine did not affect cell survival at concentrations of 0 μM to 10 μM in the A549 cells. The gap junction function between the cells was enhanced through increased Cx43 protein expression and localization of Cx43 on the membrane after berberine treatment. The intercellular dye coupli