Effects of the Pentapeptide P33 on Memory and Synaptic Plasticity in APP/PS1 Transgenic Mice: A Novel Mechanism Presenting the Protein Fe65 as a Target

Regulated intramembrane proteolysis (RIP) of the amyloid precursor protein (APP) leads to the formation of fragments, among which the intracellular domain of APP (AICD) was also identified to be a causative of early pathological events. AICD-counteracting proteins, such as Fe65, may serve as alternative therapeutic targets of Alzheimer's disease (AD). The detection of elevated levels of Fe65 in the brains of both human patients and APP transgenic mice may further strengthen the hypothesis that influencing the interaction between Fe65 and APP may have a beneficial effect on the course of AD. Based on a PXP motif, proven to bind to the WW domain of Fe65, a new pentapeptide was designed and tested. The impedimental effect of P33 on the production of beta amyloid (A beta) (soluble fraction and aggregated plaques) and on the typical features of the AD pathology (decreased dendritic spine density, synaptic markers, elevated inflammatory reactions) was also demonstrated. Significant enhancements of both learning ability and memory function were observed in a Morris water maze paradigm. The results led us to formulate the theory that P33 acts by altering the conformation of Fe65 via binding to its WW domain, consequently hindering any interactions between Fe65 and key members involved in APP processing

Structural optimization of foldamer-dendrimer conjugates as multivalent agents against the toxic effects of amyloid beta oligomers

Alzheimer's disease is one of the most common chronic neurodegenerative disorders. Despite several in vivo and clinical studies, the cause of the disease is poorly understood. Currently, amyloid β (Aβ) peptide and its tendency to assemble into soluble oligomers are known as a main pathogenic event leading to the interruption of synapses and brain degeneration. Targeting neurotoxic Aβ oligomers can help recognize the disease at an early stage or it can be a potential therapeutic approach. Unnatural β-peptidic foldamers are successfully used against many different protein targets due to their favorable structural and pharmacokinetic properties compared to small molecule or protein-like drug candidates. We have previously reported a tetravalent foldamer-dendrimer conjugate which can selectively bind Aβ oligomers. Taking advantage of multivalency and foldamers, we synthesized different multivalent foldamer-based conjugates to optimize the geometry of the ligand. Isothermal titration calorimetry (ITC) was used to measure binding affinity to Aβ, thereafter 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) based tissue viability assay and impedance-based viability assay on SH-SY5Y cells were applied to monitor Aβ toxicity and protective effects of the compounds. Important factors for high binding affinity were determined and a good correlation was found between influencing the valence and the capability of the conjugates for Aβ binding

Telített 1,3-heterociklusok gyűrű-lánc tautomériája - szubsztituenshatások vizsgálata, szintetikus alkalmazás = Ring-chain tautomerism of saturated 1,3-heterocycles - substituent effects, synthetic applications

Megállapítottuk, hogy az aminoalkil-naftolok és az aminoalkil-kinolinolok három komponensű, egylombikos Mannich-reakcióval történő előállításában az ammónium-karbamát és az ammónium-hidrogénkarbonát hatékony ammónia¬forrásként használható. Módosított Mannich reakciók során 1- és 2-naftolból illetve heterociklusos analógjaikból kiindulva számos új heterociklust állítottunk elő. Aminometilnaftolból dihidroizokinolinokkal, új pentaciklusos oxazinokat nyertünk. E közleményünket a Synfact folyóirat méltatta: http://www.thieme-connect.com/ejournals/toc/synfacts. Bizonyítottuk, hogy irodalmi adatokkal ellentétben a 2-amino-feniletanol és a 2-amino-fenilpropanol aromás aldehidekkel oldatfázisban háromkomponensű tautomer elegyet alkot. Új, környezetbarát eljárást fejlesztettünk ki spiropiperidinek előállítására. Megállapítottuk, hogy a 2-aminokarbohidrazidok és az 1-benzil-4-piperidon ciklizációja katalizátor nélkül, vízben is lezajlik, és az oldatból nagy tisztaságú termék kristályosodik ki. Nagyszámú 2,2-diszubsztituált kinazolin-4-on egyszerű, könnyen végrehajt¬ható szintézisét oldottuk meg „zöld” körülmények között vízben, vagy oldószer nélkül, 2-amino-karboxamidok ketonokkal történő gyűrűzárásával. Gyűrű-lánc tautomériát mutató közti terméken keresztül lezajlódó dominó reakcióval új típusú laktámok szintézisét oldottuk meg kiváló diasztereoszelektivitással. A kutatások során nemzetközi folyóiratokban összesen 23 közlemény jelent meg, melyek összimpakt faktora 47,6. | Ammonium carbamate and ammonium hydrogencarbonate were found to be very effective, solid sources of ammonia in the preparation of various aminoalkylnaphthols and aminoalkylquinolinols via one-pot Mannich reaction. By using a modified Mannich reaction, a great number of new heterocycles were prepared starting from 1- and 2-naphthol or their heterocyclic analogs. By reactions of aminomethylnaphthol and dihydroisoquinolines, new pentacyclic oxazines were formed. It was proved that in spite of the literature data, the condensation products of 2-aminophenylethanol or 2-aminophenylpropanol with aromatic aldehydes, participate in three-component tautomeric equilibria in solution. A new, environment-friendly process has been developed for the synthesis of spiropiperidines. The spirocyclizations of 2-aminocarbohydrazides and 1-benzyl-4-piperidone took place even in water under catalyst-free conditions, and the products crystallized out of the reaction mixture in pure form. An easy and green synthetic protocol has been developed for the preparation of 2,2-disubstituted quinazolin-4-one derivatives via ring-closures of 2-aminocarboxamides with ketones using water as solvent or solvent-free conditions. By the domino reactions of the corresponding ring-chain tautomeric intermediates, novel lactams were prepared with excellent diastereoselectivities. In frame of the research project, 23 publications (cumulative impact factor: 47.6) has been published in international scientific journals

Impact of Two Neuronal Sigma-1 Receptor Modulators, PRE084 and DMT, on Neurogenesis and Neuroinflammation in an Aβ1–42-Injected, Wild-Type Mouse Model of AD

Alzheimer’s disease (AD) is the most common form of dementia characterized by cognitive dysfunctions. Pharmacological interventions to slow the progression of AD are intensively studied. A potential direction targets neuronal sigma-1 receptors (S1Rs). S1R ligands are recognized as promising therapeutic agents that may alleviate symptom severity of AD, possibly via preventing amyloid-β-(Aβ-) induced neurotoxicity on the endoplasmic reticulum stress-associated pathways. Furthermore, S1Rs may also modulate adult neurogenesis, and the impairment of this process is reported to be associated with AD. We aimed to investigate the effects of two S1R agonists, dimethyltryptamine (DMT) and PRE084, in an Aβ-induced in vivo mouse model characterizing neurogenic and anti-neuroinflammatory symptoms of AD, and the modulatory effects of S1R agonists were analyzed by immunohistochemical methods and western blotting. DMT, binding moderately to S1R but with high affinity to 5-HT receptors, negatively influenced neurogenesis, possibly as a result of activating both receptors differently. In contrast, the highly selective S1R agonist PRE084 stimulated hippocampal cell proliferation and differentiation. Regarding neuroinflammation, DMT and PRE084 significantly reduced Aβ1–42-induced astrogliosis, but neither had remarkable effects on microglial activation. In summary, the highly selective S1R agonist PRE084 may be a promising therapeutic agent for AD. Further studies are required to clarify the multifaceted neurogenic and anti-neuroinflammatory roles of these agonists

Examination of Longitudinal Alterations in Alzheimer’s Disease-Related Neurogenesis in an APP/PS1 Transgenic Mouse Model, and the Effects of P33, a Putative Neuroprotective Agent Thereon

Neurogenesis plays a crucial role in cognitive processes. During aging and in Alzheimer’s disease (AD), altered neurogenesis and neuroinflammation are evident both in C57BL/6J, APP(Swe)/PS1(dE9) (Tg) mice and humans. AD pathology may slow down upon drug treatment, for example, in a previous study of our group P33, a putative neuroprotective agent was found to exert advantageous effects on the elevated levels of APP, Aβ, and neuroinflammation. In the present study, we aimed to examine longitudinal alterations in neurogenesis, neuroinflammation and AD pathology in a transgenic (Tg) mouse model, and assessed the putative beneficial effects of long-term P33 treatment on AD-specific neurological alterations. Hippocampal cell proliferation and differentiation were significantly reduced between 8 and 12 months of age. Regarding neuroinflammation, significantly elevated astrogliosis and microglial activation were observed in 6- to 7-month-old Tg animals. The amounts of the molecules involved in the amyloidogenic pathway were altered from 4 months of age in Tg animals. P33-treatment led to significantly increased neurogenesis in 9-month-old animals. Our data support the hypothesis that altered neurogenesis may be a consequence of AD pathology. Based on our findings in the transgenic animal model, early pharmacological treatment before the manifestation of AD symptoms might ameliorate neurological decline

Multivalent foldamer-based affinity assay for selective recognition of Aβ oligomers

Abstract Mimicking the molecular recognition functionality of antibodies is a great challenge. Foldamers are attractive candidates because of their relatively small size and designable interaction surface. This paper describes a sandwich type enzyme-linked immunoassay with a tetravalent β-peptide foldamer helix array as capture element and enzyme labeled tracer antibodies. The assay was found to be selective to β-amyloid oligomeric species with surface features transiently present in ongoing aggregation. In optimized conditions, with special emphasis on the foldamer immobilization, a detection limit of 5 pM was achieved with a linear range of 10–500 pM. These results suggest that protein mimetic foldamers can be useful tools in biosensors and affinity assays

Additional file 1 of Prednisolone Versus Colchicine for Acute Gout in Primary Care (COPAGO): protocol for a two-arm multicentre, pragmatic, prospective, randomized, double-blind, controlled clinical trial of prednisolone and colchicine for non-inferiority with a parallel group design

Additional file 1. Trial flow for patients