Brain Peptides Research Articles

Chemical Biology, Molecular Mechanism and Clinical Perspective of γ - Secretase Modulators in Alzheimers Disease

Comprehensive evidence supports that oligomerization and accumulation of amyloidogenic Aβ42 peptides in brain is crucial in the pathogenesis of both familial and sporadic forms of Alzheimer's disease. Imaging studies indicate that the buildup of Aβ begins many years before the onset of clinical symptoms, and that subsequent neurodegeneration and cognitive decline may proceed independently of Aβ. This implies the necessity for early intervention in cognitively normal individuals with therapeutic strategies that prioritize safety. The aspartyl protease γ-secretase catalyses the last step in the cellular generation of Aβ42 peptides, and is a principal target for anti-amyloidogenic intervention strategies. Due to the essential role of γ-secretase in the NOTCH signaling pathway, overt mechanism-based toxicity has been observed with the first generation of γ-secretase inhibitors, and safety of this approach has been questioned. However, two new classes of small molecules, γ-secretase modulators (GSMs) and NOTCH-sparing γ-secretase inhibitors, have revitalized γ-secretase as a drug target in AD. GSMs are small molecules that cause a product shift from Aβ42 towards shorter and less toxic Ab peptides. Importantly, GSMs spare other physiologically important substrates of the γ-secretase complex like NOTCH. Recently, GSMs with nanomolar potency and favorable in vivo properties have been described. In this review, we summarize the knowledge about the unusual proteolytic activity of γ-secretase, and the chemical biology, molecular mechanisms and clinical perspective of compounds that target the γ-secretase complex, with a particular focus on GSMs.

Preparation of magnetic core‐mesoporous shell microspheres with C8‐modified interior pore‐walls and their application in selective enrichment and analysis of mouse brain peptidome

In this paper, magnetic mesoporous silica microspheres with C8-modified interior pore-walls were prepared through a facile one-pot sol-gel coating strategy, and were successfully applied for selective enrichment of endogenous peptides in mouse brain for peptidome analysis. Through the one-pot sol-gel approach with surfactant (CTAB) as a template, tetraethyl orthosilicate (TEOS) and n-ctyltriethoxysilane (C8TEOS) as the precursors, C8-modified magnetic mesoporous microspheres (C8-Fe(3)O(4)@mSiO(2)) consisting magnetic core and mesoporous silica shell with C8-groups exposed in the mesopore channels were synthesized. The obtained microspheres possess highly open mesopores of 3.4 nm, high surface area (162.5 m(2)/g), large pore volume (0.17 cm(3)/g), excellent magnetic responsivity (56.3 emu/g) and good dispersibility in aqueous solution. Based on the abundant surface silanol groups, functional C8 groups and the strong magnetic responsivity of the core-shell C8-Fe(3) O(4) @mSiO(2) microspheres, efficient and fast enrichment of peptides was achieved. Additionally, the C8-Fe(3)O(4)@mSiO(2) microspheres exhibit excellent performance in selective enrichment of endogenous peptides from complex samples that are consist of peptides, large proteins and other compounds, including human serum and mouse brain followed by automated nano-LC-ESI-MS/MS analysis. These results indicate C8-Fe(3)O(4)@mSiO(2) microspheres would be a potential candidate for endogenous peptides enrichment and biomarkers discovery in peptidome analysis.

Characterization of Novel RFamide Peptides in the Central Nervous System of the Brown Hagfish: Isolation, Localization, and Functional Analysis

RFamide (RFa) peptides play various important roles in the central nervous system in both invertebrates and vertebrates. However, there is no evidence of the existence of any RFamide peptide in the brain of hagfish, one of the oldest lineages of vertebrates. In this study, we sought to identify novel RFamide peptides from the brains of hagfish (Paramyxine atami). We identified four novel RFamide peptides, which had the C-terminal Pro-Gln-Arg-Phe-NH2 structure. cDNA cloning revealed that the identified RFamide peptides are encoded in two types of cDNA. Molecular phylogenetic analysis of the two precursors indicated that the hagfish RFamide peptides belong to the PQRFamide peptide group that includes mammalian neuropeptide FF and AF. Based on immunohistochemistry and in situ hybridization, hagfish PQRFamide peptide precursor mRNA and its translated peptides were localized in the infundibular nucleus of the hypothalamus. Immunoreactive fibers were terminated on blood vessels in the infundibular nucleus. Dense immunoreactive fibers were also observed in other brain regions. We further showed that one of the hagfish PQRFamide peptides significantly stimulated the expression of gonadotropin-β mRNA in the cultured hagfish pituitary. These results indicate that the control mechanism of gonadotropin expression by a hypothalamic neuropeptide evolved in the agnathan brain. This is the first evidence describing the identification of RFamide peptides in the hagfish brain. This is also the first report showing the regulation of gonadotropin expression by a homolog of neuropeptide FF that belongs to the PQRFamide peptide group in any vertebrate.

Infusions of neuropeptide Y into the lateral septum reduce anxiety-related behaviors in the rat

Neuropeptide Y (NPY) is one of the most abundant peptides in mammalian brain and NPY-like-immunoreactivity is highly expressed in the lateral septum, an area extensively involved in anxiety regulation. NPY counteracts the neurochemical and behavioral responses to acute threat in animal models, and intracerebroventricular (i.c.v.) administration of NPY at low doses is anxiolytic. Less is known about the specific contributions of the lateral septum to NPY-mediated anxiety regulation. In Experiment 1, the effects of infusions of NPY (1.5μg) into the lateral septum were investigated in three animal models of anxiety: the elevated plus-maze, novelty-induced suppression of feeding, and shock-probe burying tests. Experiment 2 examined the role of the NPY Y1 receptor in these models by co-infusing the Y1 antagonist BIBO 3304 (0.15μg, 0.30μg) with NPY into the lateral septum. In the elevated plus-maze, there were no changes in rats' open arm exploration, the index of anxiety reduction in this test. In the novelty-induced suppression of feeding test, rats infused with NPY showed decreases in the latency to consume a palatable snack in a novel (but not familiar) environment, suggesting a reduction in anxiety independent of increases in appetite. This anxiolysis was attenuated by co-infusion with BIBO 3304 (0.30μg) in Experiment 2. Lastly, rats infused with NPY showed decreases in the duration of burying behavior in the shock-probe burying test, also indicative of anxiety reduction. However, unlike in the feeding test, BIBO 3304 did not attenuate the NPY-induced anxiolysis in the shock-probe test. It is concluded that NPY produces anxiolytic-like actions in the lateral septum in two animal models of anxiety: the novelty-induced suppression of feeding, and shock-probe burying tests, and that this anxiolysis is dependent on Y1 receptor activation in the feeding test.

Interaction between amyloid precursor protein and Nogo receptors regulates amyloid deposition

Excessive production or accumulation of β-amyloid (Aβ) peptides in human brains leads to increased amyloid deposition and cognitive dysfunction, which are invariable pathological features in patients with Alzheimer's disease (AD). Many cellular factors can regulate the production of Aβ. In this study, we show that a family of proteins named Nogo receptor proteins (NgR1 to NgR3) regulates Aβ production via interaction with amyloid precursor protein (APP). Further mapping of the interacting domain indicates that a small region adjacent to the BACE1 cleavage site of APP mediates interaction of APP with Nogo receptor proteins. Our results also indicate that increased interaction between Nogo receptor and APP reduces surface expression of APP and favors processing of APP by BACE1. When NgR2 was ablated in AD transgenic mice expressing Swedish APP and PS1ΔE9, amyloid deposition was clearly reduced (0.66% of total measured area in APP(swe)/PS1ΔE9/NgR2(-/-) mice vs. 0.76% of total measured area in APP(swe)/PS1ΔE9 mice). Our results demonstrate that down-regulation of NgR expression is a potential approach for inhibiting amyloid deposition in AD patients.

Neural and hormonal control of food hoarding

Many animals hoard food, including humans, but despite its pervasiveness, little is known about the physiological mechanisms underlying this appetitive behavior. We summarize studies of food hoarding in humans and rodents with an emphasis on mechanistic laboratory studies of species where this behavior importantly impacts their energy balance (hamsters), but include laboratory rat studies although their wild counterparts do not hoard food. The photoperiod and cold can affect food hoarding, but food availability is the most significant environmental factor affecting food hoarding. Food-deprived/restricted hamsters and humans exhibit large increases in food hoarding compared with their fed counterparts, both doing so without overeating. Some of the peripheral and central peptides involved in food intake also affect food hoarding, although many have not been tested. Ad libitum-fed hamsters given systemic injections of ghrelin, the peripheral orexigenic hormone that increases with fasting, mimics food deprivation-induced increases in food hoarding. Neuropeptide Y or agouti-related protein, brain peptides stimulated by ghrelin, given centrally to ad libitum-fed hamsters, duplicates the early and prolonged postfood deprivation increases in food hoarding, whereas central melanocortin receptor agonism tends to inhibit food deprivation and ghrelin stimulation of hoarding. Central or peripheral leptin injection or peripheral cholecystokinin-33, known satiety peptides, inhibit food hoarding. Food hoarding markedly increases with pregnancy and lactation. Because fasted and/or obese humans hoard more food in general, and more high-density/high-fat foods specifically, than nonfasted and/or nonobese humans, understanding the mechanisms underlying food hoarding could provide another target for behavioral/pharmacological approaches to curb obesity.

Unacylated ghrelin is associated with changes in body composition and body fat distribution during long-term exercise intervention

Ghrelin, a gut-brain peptide involved in energy homeostasis, circulates predominantly (>90%) in unacylated form. Previous studies, however, have focused on total and acylated ghrelin, and the role of unacylated ghrelin (UAG) is not well understood. Particularly, the association of UAG with weight loss and changes in body composition in adults remains unclear. We hypothesized that exercise-associated increase in UAG level is associated with weight loss, favorable changes in body composition, and body fat distribution. A prospective study of 552 young men (mean age 19.3 and range 19-28 years) undergoing military service with structured 6-month exercise training program. Exercise performance, body composition, and biochemical measurements were obtained at baseline and follow-up. Association between changes in UAG levels and body composition and body fat distribution were evaluated. An increase in UAG level during the exercise intervention was associated with reduced weight, fat mass (FM), fat percentage (fat %), and waist circumference, but not with fat-free mass. Inverse associations of changes in UAG level with changes in waist circumference and fat % were independent of weight at baseline, and changes in weight and exercise performance. Associations of changes in UAG level with waist circumference were significantly stronger than with fat % after the adjustment for confounding variables. UAG is associated with changes in body weight and body composition during an intensive long-term exercise intervention in young men. The association of UAG levels with changes in central obesity was stronger than with total FM.

TRH-Like Peptides

TRH-like peptides are characterized by substitution of basic amino acid histidine (related to authentic TRH) with neutral or acidic amino acid, like glutamic acid, phenylalanine, glutamine, tyrosine, leucin, valin, aspartic acid and asparagine. The presence of extrahypothalamic TRH-like peptides was reported in peripheral tissues including gastrointestinal tract, placenta, neural tissues, male reproductive system and certain endocrine tissues. Work deals with the biological function of TRH-like peptides in different parts of organisms where various mechanisms may serve for realisation of biological function of TRH-like peptides as negative feedback to the pituitary exerted by the TRH-like peptides, the role of pEEPam such as fertilization-promoting peptide, the mechanism influencing the proliferative ability of prostatic tissues, the neuroprotective and antidepressant function of TRH-like peptides in brain and the regulation of thyroid status by TRH-like peptides.

DNA Immunization Against Amyloid beta 42 has High Potential as Safe Therapy for Alzheimer’s Disease as it Diminishes Antigen-Specific Th1 and Th17 Cell Proliferation

The pathogenesis of Alzheimer's disease (AD) has been strongly associated with the accumulation of amyloid beta (Aβ) peptides in brain, and immunotherapy targeting Aβ provides potential for AD prevention. A clinical trial in which AD patients were immunized with Aβ42 peptide was stopped when 6% of participants showed meningoencephalitis, apparently due to an inflammatory Th1 immune response. Previously, we and other have shown that Aβ42 DNA vaccination via gene gun generates a Th2 cellular immune response, which was shown by analyses of the respective antibody isotype profiles. We also determined that in vitro T cell proliferation in response to Aβ42 peptide re-stimulation was absent in DNA Aβ42 trimer-immunized mice when compared to Aβ42 peptide-immunized mice. To further characterize this observation prospectively and longitudinally, we analyzed the immune response in wild-type mice after vaccination with Aβ42 trimer DNA and Aβ42 peptide with Quil A adjuvant. Wild-type mice were immunized with short-term (1-3× vaccinations) or long-term (6× vacinations) immunization strategies. Antibody titers and isotype profiles of the Aβ42 specific antibodies, as well as cytokine profiles and cell proliferation studies from this longitudinal study were determined. Sufficient antibody titers to effectively reduce Aβ42, but an absent T cell proliferative response and no IFNγ or IL-17 secretion after Aβ42 DNA trimer immunization minimizes the risk of inflammatory activities of the immune system towards the self antigen Aβ42 in brain. Therefore, Aβ42 DNA trimer immunization has a high probability to be effective and safe to treat patients with early AD.

Endogenous amyloid‐β is necessary for hippocampal synaptic plasticity and memory

The goal of this study was to investigate the role of endogenous amyloid-β peptide (Aβ) in healthy brain. Long-term potentiation (LTP), a type of synaptic plasticity that is thought to be associated with learning and memory, was examined through extracellular field recordings from the CA1 region of hippocampal slices, whereas behavioral techniques were used to assess contextual fear memory and reference memory. Amyloid precursor protein (APP) expression was reduced through small interfering RNA (siRNA) technique. We found that both antirodent Aβ antibody and siRNA against murine APP reduced LTP as well as contextual fear memory and reference memory. These effects were rescued by the addition of human Aβ₄₂, suggesting that endogenously produced Aβ is needed for normal LTP and memory. Furthermore, the effect of endogenous Aβ on plasticity and memory was likely due to regulation of transmitter release, activation of α7-containing nicotinic acetylcholine receptors, and Aβ₄₂ production. Endogenous Aβ₄₂ is a critical player in synaptic plasticity and memory within the normal central nervous system. This needs to be taken into consideration when designing therapies aiming at reducing Aβ levels to treat Alzheimer disease.

Structures of Human Golgi-resident Glutaminyl Cyclase and Its Complexes with Inhibitors Reveal a Large Loop Movement upon Inhibitor Binding

Aberrant pyroglutamate formation at the N terminus of certain peptides and proteins, catalyzed by glutaminyl cyclases (QCs), is linked to some pathological conditions, such as Alzheimer disease. Recently, a glutaminyl cyclase (QC) inhibitor, PBD150, was shown to be able to reduce the deposition of pyroglutamate-modified amyloid-β peptides in brain of transgenic mouse models of Alzheimer disease, leading to a significant improvement of learning and memory in those transgenic animals. Here, we report the 1.05-1.40 Å resolution structures, solved by the sulfur single-wavelength anomalous dispersion phasing method, of the Golgi-luminal catalytic domain of the recently identified Golgi-resident QC (gQC) and its complex with PBD150. We also describe the high-resolution structures of secretory QC (sQC)-PBD150 complex and two other gQC-inhibitor complexes. gQC structure has a scaffold similar to that of sQC but with a relatively wider and negatively charged active site, suggesting a distinct substrate specificity from sQC. Upon binding to PBD150, a large loop movement in gQC allows the inhibitor to be tightly held in its active site primarily by hydrophobic interactions. Further comparisons of the inhibitor-bound structures revealed distinct interactions of the inhibitors with gQC and sQC, which are consistent with the results from our inhibitor assays reported here. Because gQC and sQC may play different biological roles in vivo, the different inhibitor binding modes allow the design of specific inhibitors toward gQC and sQC.

Parent-Child Interactions Affected by Gene Variant

Back to table of contents Previous article Next article Clinical & Research NewsFull AccessParent-Child Interactions Affected by Gene VariantJoan Arehart-TreichelJoan Arehart-TreichelSearch for more papers by this authorPublished Online:1 Apr 2011https://doi.org/10.1176/pn.46.7.psychnews_46_7_16_2AbstractAn intriguing new study has found that opioid peptides—brain peptides that respond to pain—influence parent-child relationships.The study sample—226 youth aged 9 to 17—was derived from a larger investigation of psychiatric illness and service use in youth in four rural North Carolina counties that have high poverty rates. All participating children and teens were genotyped for the gene that makes the mu-opioid receptor, to which opioid peptides attach. Out of the 226 children, two-thirds had the A variant of the gene (that is, A/A), while the remaining third had the G variant (either G/G or G/A). Each child and one of its parents (usually the mother) were then interviewed using the Child and Adolescent Psychiatric Assessment to obtain information about three aspects of their relationship during the previous three months—separation anxiety, enjoyment of parent-child activities, and parent-child arguments. The researchers then assessed, after taking the youngsters' age and gender into consideration, whether there was a significant link between the mu-opioid receptor gene variant that a child possessed and his or her relationship with the parent during the previous three months. There was such a relationship, they found. Interview findings indicated that children with the G variant indicated that they enjoyed parent-child activities significantly more, had significantly fewer parent-child arguments, and experienced significantly less separation anxiety than did children with the A variant. Furthermore, the findings held even when mental health problems, substance abuse problems, or criminal convictions of the parents were considered. "I think our findings may help explain why some children faced with adversity continue to do well and maintain a good relationship with their parents," William Copeland, Ph.D., an associate professor of psychiatry at Duke University and the lead investigator, told Psychiatric News. "We think this variant may be important for understanding social interactions, which are disrupted in many common psychiatric disorders … . It is probably premature, however, to start thinking about clinical implications. As cautious scientists, we are still interested in seeing this finding replicated in other samples." In addition to benefiting parent-child relationships, the G variant of the opioid receptor gene also seems to confer another advantage—less pain sensitivity—and a disadvantage—an increased risk of substance dependence in adolescence and early adulthood, other researchers have found. The study was funded by the National Institutes of Health.An abstract of "Child Mu-Opioid Receptor Gene Variant Influences Parent-Child Relations" is posted at <www.nature.com/npp/journal/vaop/ncurrent/abs/npp2010251a.html>. ISSUES NewArchived

There are Abundant Antimicrobial Peptides in Brains of Two Kinds ofBombinaToads

It is well-known that there is a large amount of antimicrobial peptides in amphibian skins but few antimicrobial peptides are found in amphibian brains. Twenty-two and four antimicrobial peptides were purified and characterized from the brain homogenate of Bombina maxima and B. microdeladigitora, respectively. One hundred fifty-eight cDNA clones encoding 79 antimicrobial peptides were isolated from brain cDNA libraries of B. maxima and B. microdeladigitora. These antimicrobial peptides belong to two peptide groups (maximin and maximin-H). Twenty of them are identical to previously reported antimicrobial peptides (maximin 1-8, 10, 11, maximin H1, 3-5, 7, 9, 10, 12, 15, 16) from B. maxima skin secretions. Fifty-nine of them are novel antimicrobial peptides. Some of these antimicrobial peptides showed strong antimicrobial activities against tested microorganism strains including Gram-positive and -negative bacteria and fungi. The current diversity in peptide coding cDNA sequences is, to our knowledge, the most extreme yet described for any animal brains. The extreme diversity may give rise to interest to prospect the actual functions of antimicrobial peptides in amphibian brains.

Comparison of extraction methods for peptidomics analysis of mouse brain tissue

The peptidome encompasses all the peptides present in a particular cell, tissue or organism at a particular point in time. Neuropeptidomics studies the peptidome of the nervous system and will become increasingly important in neuroscience research. Novel peptides can be discovered and, when applied to disease models, key players in pathophysiological mechanisms will be identified. That way, they can serve as drug targets or biomarkers. Presently, different extraction protocols are in use, but no consensus has been reached on what fixation and extraction protocol is best suited for brain tissue. Therefore, in this article we compare different methods for quenching of proteolytic activity (snap-freezing of whole mouse in liquid nitrogen immediately after cervical dislocation, freezing of the dissected brain in 2-methyl-butane and heat denaturation of the tissue by microwave treatment) in combination with different extraction methods. The protocol that combines submersion in liquid nitrogen with extraction in 0.25% acetic acid results in the highest number of unique identifications, a high conservation of posttranslational modifications, the best reproducibility between duplicate samples and the best comparison with former studies on mouse brain peptides. For these reasons, we recommend the use of this protocol in future neuropeptidomics studies.

Intraventricular administration of neuropeptide S has reward-like effects

Neuropeptide S (NPS) is an endogenous brain peptide produced by neurons located in the lower brainstem, and functional studies suggest that NPS has arousing effects. Because its receptors are found in reward-associated regions throughout the brain, we evaluated whether intraventricular NPS injections elicit reward-related effects in rats. Rats increased lever presses that led to intraventricular administration of NPS (0.34–34 pmol per infusion) in a dose dependent manner, with a cue-assisted procedure. Cue-assisted self-administration of NPS was decreased by systemic administration of the dopamine receptor antagonist SCH 23390 (0.025 mg/kg, i.p.) or the hypocretin-1 (orexin-1) receptor antagonist SB 334867 (20 mg/kg, i.p.). In addition, intraventricular NPS injections (1000 pmol) induced conditioned place preference, whereas a lower dose (100 pmol) of NPS induced conditioned place aversion. Finally, NPS injections (100–1000 pmol) acutely facilitated locomotor activity, whereas repeated NPS injections did not lead to locomotor sensitization. Our data suggest that intraventricular NPS injections have reward-like effects in that NPS weakly facilitates seeking and induces positive reinforcement. These effects may depend on intact dopamine and hypocretin systems.

Identification, localization and expression of LPXRFamide peptides, and melatonin-dependent induction of their precursor mRNA in the newt brain

The existence of RFamide peptides with a C-terminal LPXRFamide (X=L or Q) motif has been identified in the brain of various vertebrate species. However, the presence of LPXRFamide peptides in the urodele brain is not yet known. In this study, we cloned a cDNA encoding the precursor of LPXRFamide peptides from the newt brain by a combination of 3' and 5' rapid amplification of cDNA ends. The deduced LPXRFamide peptide precursor consisted of 233 amino acid residues, encoding four putative LPXRFamide peptides. All the peptide sequences were flanked by a glycine C-terminal amidation signal and basic amino acid on each end as an endoproteolytic site. Mass spectrometric analyses detected a nonapeptide, two decapeptides and an octapeptide produced from the precursor polypeptide in the brain as endogenous ligands. In situ hybridization further revealed the cellular localization of newt LPXRFamide (nLPXRFa) precursor mRNA in the suprachiasmatic nucleus (SCN) in the newt hypothalamus. Immunocytochemistry showed a cluster of cell bodies restricted to the SCN and their terminals in the median eminence. To understand the regulatory mechanism of nLPXRFa peptide expression, we further analyzed the effect of melatonin on the expression of nLPXRFa precursor mRNA. Melatonin administration to newts increased the expression of nLPXRFa precursor mRNA in the diencephalon. These results indicate that the urodele hypothalamus possesses LPXRFamide peptides and the expression of LPXRFamide peptides is regulated by melatonin. The localization of nLPXRFa peptides further suggests that these peptides may be involved in the regulation of pituitary hormone release in newts.

Cholecystokinin-33 inhibits meal size and prolongs the subsequent intermeal interval

There are various forms of the satiety gut–brain peptide cholecystokinin (CCK), a short, widely utilized form or CCK-8, and a long, putatively more effective form or CCK-33. The issue of which of these forms is a more effective satiety peptide is not resolved. Here, we compared the satiety responses, including the sizes of the first three meals (MS) and intermeal intervals (IMI) as well as their calculated satiety ratios (SR), evoked by both peptides. CCK-8 and 33 (1, 3 and 5 nmol/kg, i.p) reduced the size of the first meal similarly, only CCK-33 prolonged the first IMI and increased SR and both peptides failed to affect second and third MS and IMI. As such, CCK-33 is a more effective satiety peptide than CCK-8. The current results confirm previous findings which showed that both peptides reduce food intake by inhibiting meal size, whereas only CCK-33 reduces food intake by prolonging the intermeal interval.

Current biochemistry, molecular biology, and clinical relevance of natriuretic peptides

The mammalian natriuretic peptide family consists of atrial (ANP), brain [B-type; BNP] and C-type natriuretic peptide (CNP) and three receptors, natriuretic receptors-A (NPR-A), -B (NPR-B) and -C (NPR-C). Both ANP and BNP are abundantly expressed in the heart and are secreted mainly from the atria and ventricles, respectively. By contrast, CNP is mainly expressed in the central nervous system, bone and vasculature. Plasma concentrations of both ANP and BNP are elevated in patients with cardiovascular disease, though the magnitude of the increase in BNP is usually greater than the increase in ANP. This makes BNP is a clinically useful diagnostic marker for several pathophysiological conditions, including heart failure, ventricular remodeling and pulmonary hypertension, among others. Recent studies have shown that in addition to BNP-32, proBNP-108 also circulates in human plasma and that levels of both forms are increased in heart failure. Furthermore, proBNP-108 is O-glycosylated and circulates at higher levels in patients with severe heart failure. In this review we discuss recent progress in our understanding of the biochemistry, molecular biology and clinical relevance of the natriuretic peptide system.

Overexpression of Glutaminyl Cyclase, the Enzyme Responsible for Pyroglutamate Aβ Formation, Induces Behavioral Deficits, and Glutaminyl Cyclase Knock-out Rescues the Behavioral Phenotype in 5XFAD Mice

Pyroglutamate-modified Aβ (AβpE3-42) peptides are gaining considerable attention as potential key players in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Overexpressing AβpE3-42 induced a severe neuron loss and neurological phenotype in TBA2 mice. In vitro and in vivo experiments have recently proven that the enzyme glutaminyl cyclase (QC) catalyzes the formation of AβpE3-42. The aim of the present work was to analyze the role of QC in an AD mouse model with abundant AβpE3-42 formation. 5XFAD mice were crossed with transgenic mice expressing human QC (hQC) under the control of the Thy1 promoter. 5XFAD/hQC bigenic mice showed significant elevation in TBS, SDS, and formic acid-soluble AβpE3-42 peptides and aggregation in plaques. In 6-month-old 5XFAD/hQC mice, a significant motor and working memory impairment developed compared with 5XFAD. The contribution of endogenous QC was studied by generating 5XFAD/QC-KO mice (mouse QC knock-out). 5XFAD/QC-KO mice showed a significant rescue of the wild-type mice behavioral phenotype, demonstrating the important contribution of endogenous mouse QC and transgenic overexpressed QC. These data clearly demonstrate that QC is crucial for modulating AβpE3-42 levels in vivo and prove on a genetic base the concept that reduction of QC activity is a promising new therapeutic approach for AD.

A pilot trial of the microtubule-interacting peptide (NAP) in mice overexpressing alpha-synuclein shows improvement in motor function and reduction of alpha-synuclein inclusions

Abnormal accumulation of α-synuclein is associated with several neurodegenerative disorders (synucleinopathies), including sporadic Parkinson's disease (PD). Genetic mutations and multiplication of α-synuclein cause familial forms of PD and polymorphisms in the α-synuclein gene are associated with PD risk. Overexpression of α-synuclein can impair essential functions within the cell such as microtubule-dependent transport, suggesting that compounds that act on the microtubule system may have therapeutic benefit for synucleinopathies. In this study, mice overexpressing human wildtype α-synuclein under the Thy1 promoter (Thy1-aSyn) and littermate wildtype control mice were administered daily the microtubule-interacting peptide NAPVSIPQ (NAP; also known as davunetide or AL-108) intranasally for 2 months starting at 1 month of age, in a regimen known to produce effective concentrations of the peptide in mouse brain. Motor performance, coordination, and activity were assessed at the end of treatment. Olfactory function, which is altered in PD, was measured 1 month later. Mice were sacrificed at 4.5 months of age, and their brains examined for proteinase K-resistant α-synuclein inclusions in the substantia nigra and olfactory bulb. NAP-treated Thy1-aSyn mice showed a 38% decrease in the number of errors per step in the challenging beam traversal test and a reduction in proteinase K-resistant α-synuclein inclusions in the substantia nigra compared to vehicle treated transgenics. The data indicate a significant behavioral benefit and a long lasting improvement of α-synuclein pathology following administration of a short term (2 months) NAP administration in a mouse model of synucleinopathy.