Béta-amiloid peptidek aggregációja és kölcsönhatása fehérjékkel; új neuroprotektív vegyületek alkalmazása az Alzheimer-kór megelőzésére = Beta-amyloid aggregation and interaction with proteins; novel neuroprotective compounds for prevention of Alzheimer's disease

Uj, standardizalhato modszert dolgoztunk ki toxikus �beta-amiloid (Abeta) 1-42 peptid oligomerek előallitasara, a preparalt oligomereket fiziko-kemiai modszerekkel jellemeztuk. Ket uj neuroprotektiv peptidmimetikum vegyuletcsaladot talaltunk, ezek az anyagok megvedik a neuronokat az Alzheimer-kor (AK) allatmodelljeben az Abeta neurotoxikus hatasatol. Mindket vegyuletcsoportot szabadalmilag vedjuk, mint az AK potencialis gyogyszerjelolt vegyuleteit. Uj ex vivo modszert dolgoztunk ki az Abeta peptidek toxicitasanak meresere (patkany hippocampus szelet, MTT-teszt), a modszer alkalmas az uj neuroprotektiv vegyuleteink aktivitasmeresere is. Az ex vivo hippocampus szeleteket sikerrel alkalmaztuk a neuronalis plaszticitas (LTP) meresere, az Abeta-toxicitas meghatarozasara, multielektrod array (MEA) technikaval. In vivo, egysejt-elvezeteses elektrofiziologiai meresekkel bizonyitottuk az uj peptidmimetikumaink neuroprotektiv hatasat. Proteomikai modszerekkel azonositottuk az Abeta peptidekkel kolcsonhatasba lepő feherjeket, ezek elsősorban plazmamembran, ill. intraneuronalis feherjek (mitokondrium, endoplazmas reticulum, mikrotubularis rendszer). Az intraneuronalis feherjek es az Abeta peptidek kolcsonhatasai kulcsszerepet jatszhatnak az AK patogeneziseben. Igazoltuk, hogy a Zn2+ ionok toxikus Abeta-aggregatumok kepződeset indukaljak. Az AK transzgen allatmodelljen bizonyitottuk, hogy a Zn-kelatorok (pl. Perindopril) neuroprotektiv hatasuak. Uj AK-allatmodellt dolgoztunk ki az Abeta oligomerek icv bevitelevel. | A new method was introduced for the preparation of toxic beta-amyloid (Abeta) 1-42 oligomers, these assemblies were characterized with physicochemical methods. Two families of novel neuroprotective peptidomimetics were found, these substances protect neurons against the toxic effect of Abeta in tg mouse models of Alzheimer’s disease (AD). Both groups of the novel substances will be patented as putative drug candidates for AD treatment. A new ex vivo method was introduced for toxicity measurement of Abeta peptides (rat hippocampal slices, MTT-assay); this method proved to be suitable for activity measurement of the novel neuroprotective substances. Hippocampal slices were successfully used for measurement of neuronal plasticity (LTP) for demonstrating neurotoxicity of Abeta aggregates, applying multielectrode array (MEA) technique. The neuroprotective effect of our novel peptidomimetics was demonstrated also in vivo, using one-cell electrophysiology. Proteomic methods were used for identification of proteins interacting with Abeta peptides; these are mainly plasma membrane and intraneuronal (mitochondrial, endoplasmatic reticular and microtubular) proteins. Interaction of intracellular proteins with Abeta may play key role in AD pathogenesis. The role of Zn2+ ions in formation of toxic Abeta-aggregates was demonstrated. Zn2+-chelators (e.g. Perindopril) were neuroprotective in a tg-mouse model of AD. A new AD rat model was introduced using icv administration of synthetic Abeta oligomers.