Title Mogućnost razvoja netransgeničnoga štakorskoga modela tauopatije primjenom tau oligomera u entorinalnu moždanu koru Title (english) Development and characterization of a non-transgenic rat model of tauopathy induced by injection of tau protein into the entorhinal cortex Author Lea Langer Horvat Mentor Goran Šimić (mentor)Committee member Melita Šalković-Petrišić (predsjednik povjerenstva)Committee member Fran Borovečki (član povjerenstva)Committee member Ninoslav Mimica (član povjerenstva)Committee member Dubravka Švob Štrac (član povjerenstva)Committee member Dubravka Hranilović (član povjerenstva)Granter University of Zagreb Defense date and country 2022-12-14, Croatia Scientific / art field, BIOMEDICINE AND HEALTHCARE Universal decimal classificationUDC ) 61 - Medical sciences Abstract U istraživanju Alzheimerove bolesti (AD) najviše su korišteni transgenični animalni modeli koji zapravo nisu pogodni za istraživanje složenih procesa sporadične AD, koja čini više od 95% svih slučajeva AD-a. Cilj je ovog istraživanja bio karakterizacija netransgeničnog štakorskog modela tauopatije koji će pridonijeti boljem razumijevanju patologije transsinaptičkog širenja i agregacije tau proteina u AD-u i mogućem iznalaženju novih terapijskih ciljeva za sprječavanje nastanka te zaustavljanje širenja navedenih patoloških promjena. Budući da najranije neurofibrilarne promjene u mozgu osoba s AD-om nastaju u moždanom deblu i entorinalnoj moždanoj kori, odakle se šire duž anatomski povezanih područja, za proučavanje njezinog transsinaptičkog širenja provedena je jednostrana stereotaksijska inokulacija tau oligomera ili sintetskih tau fibrila u medijalni dio entorinalne moždane kore Wistar štakora. Inokulacija tau oligomera i tau fibrila uzrokovala je progresiju neurofibrilarnih promjena iz entorinalne moždane kore u druga, s njom povezana područja mozga, slično kao što se to događa i u mozgu čovjeka s AD-om. Nastanak i širenje patološki promijenjenog tau proteina, kako je pokazano pomoću AT8 protutijela na relativno velik epitop i vjerojatno strukturno važan dio tau proteina fosforiliran na serinu199, serinu202 i treoninu205, događalo se brže u životinja inokuliranih tau fibrilima u odnosu na životinje kojima su bili inokulirani tau oligomeri. U životinja kojima su inokulirani tau oligomeri, zbog sporijeg širenja bilo je potrebno jedanaest mjeseci za zahvaćanje svih područja mozga. Osim navedenih neurofibrilarnih promjena, inokulacija tau fibrila i tau oligomera izazvala je i pojavu konformacijski promijenjenog tau proteina, stvaranje inkluzija pozitivnih na histokemijska bojenja po Gallyasu i Bielschowskom koja su potvrdila akumuliranje fosforiliranih tau proteina, nakupljanje amiloida-β, gubitak sinapsi u hipokampusu i tim promjenama odgovarajuće značajne kognitivne deficite potvrđene testovima otvorenog polja, prepoznavanja novog objekta, prepoznavanja nove lokacije objekta i T-labirint testom.
Abstract (english) Transgenic mouse models have been extensively used in Alzheimer’s disease (AD) research, although they are limited in their ability to replicate the complex process of sporadic AD, which concerns well over 95% of all AD cases. In this study, we aimed to characterize a non-transgenic rat model of tauopathy that can contribute to a better understanding of possible pathological changes, trans-synaptic spread and tau protein aggregation in AD, and find new therapeutic targets to prevent the onset or stop the spread of those pathological changes. To analyze trans-synaptic spread in Wistar rats, unilateral inoculation of tau oligomers or synthetic tau fibrils into the medial entorhinal cortex was performed, since it has been shown that the earliest neurofibrillary changes in AD brains originate in the brainstem and entorhinal cortex from where they further propagate along anatomically connected regions. Inoculation of tau oligomers and tau fibrils caused the progression of neurofibrillary changes from the entorhinal cortex to other connected brain regions, similar to AD-related changes outlined in the human brain. The development and spreading of supposedly the earliest tau pathological change, as revealed by using the AT8 monoclonal antibody to the relatively complex epitope and likely structurally important part of tau protein phosphorylated at Ser199, Ser202, and Thr205 residues, occurred much faster in animals inoculated with tau fibrils than in animals inoculated with tau oligomers. Due to a slower propagation, in animals inoculated with tau oligomers it took eleven months for all areas of the brain to be affected. In addition to neurofibrillary changes, stereotaxic inoculation of tau fibrils and tau oligomers caused the appearance of conformationally altered tau protein, formation of Gallyas- and Bielschowsy-positive inclusions that confirmed the accumulation of phosphorylated tau proteins, accumulation of amyloid , loss of synapses in the hippocampus, and significant corresponding cognitive deficits documented by using the open field test, novel object location test, novel object recognition test and T-maze test.
Keywords
animalni netransgeni model
neurofibrilarna degeneracija
prostorno radno pamćenje
spoznajne sposobnosti
tau fibrili
tau oligomeri
tau protein
tauopatije
Wistar štakor
Keywords (english)
animal non-transgenic model
cognition
neurofibrillary degeneration
spatial working memory
tau fibrils
tau oligomers
tau protein
tauopathies
Wistar rat
Language croatian URN:NBN urn:nbn:hr:105:797971 Project Number: IP-2014-09-9730 Project Number: KK.01.1.1.01.0007 Study programme Title: Neuroscience Type of resource Text Extent 219 str. File origin Born digital Access conditions Embargoed access Terms of use Created on 2023-01-30 12:41:44
