20.500.12556/RUL-161090 Diagnostični in prognostični pomen posttranslacijskih sprememb beljakovine tau pri nevrodegenerativnih boleznih Diagnostic and prognostic importance of tau protein postranslational modifications in neurodegenerative diseases Nevrodegenerativne bolezni so heterogena skupina bolezni z napredujočo okvaro in propadom nevronov, ki ga povezujemo s kopičenjem bolezensko spremenjenih beljakovin v živčevju. V okviru doktorskega dela smo prikazali uporabnost in pojasnjevali pomen potranslacijsko spremenjenega proteina tau kot biološkega označevalca pri Alzheimerjevi in drugih boleznih s predhodno opisanimi agregacijami hiperfosforiliranega proteina tau (p-tau). Razvili smo metode za določanje N-terminalnih fragmentov različnih zvrsti p-tau v likvorju na osnovi tehnologije Simoa in njihovo diagnostično uporabnost ocenili v dveh kliničnih kohortah bolnikov z Alzheimerjevo boleznijo. Koncentracije N-terminalnih p-tau181 in p-tau217 so bile zvišane že zgodaj v poteku Alzheimerjeve bolezni, pri bolnikih z blago kognitivno motnjo, pri katerih smo s trenutno uveljavljenimi označevalci zaznali le znižano razmerje amiloida beta v likvorju. Novi označevalci so bolje razlikovali med blago kognitivno motnjo v okviru Alzheimerjeve bolezni ali zaradi drugega vzroka. Pokazali smo večji potencial N-terminalnih p-tau181, p-tau217 in p-tau231 za prepoznavo spremljajočih tauopatij pri zanesljivi Creutzfeldt-Jakobovi bolezni. Koncentracije N-terminalnih ptau so bile najvišje med bolniki s Creutzfeldt-Jakobovo in dodatno nevropatološko potrjeno Alzheimerjevo boleznijo, a zvišane glede na kontrolno skupino tudi pri bolnikih s sočasno primarno starostno tauopatijo ter bolnikih brez dodatnih patologij. Opažali smo razlike v N-terminalnih ptau181 in p-tau231 med podtipi Creutzfeldt-Jakobove bolezni in predpostavljali, da bi lahko odražale s prionsko boleznijo povezano kopičenje p-tau. V likvorju bolnikov z različnimi oblikami multiple skleroze smo ugotavljali višje koncentracije Nterminalnih p-tau pri primarno napredujoči obliki bolezni v primerjavi z obliko z zagoni ter korelacijo s trajanjem bolezni in klinično lestvico za oceno stopnje prizadetosti, kar nakazuje možno spremembo v obsegu fosforilacije tau z napredovanjem multiple skleroze. Z našimi raziskavami smo pridobili nove, zgodnje označevalce patološko spremenjene beljakovine tau, s katerimi bi lahko izboljšali razumevanje nevrodegenerativnih procesov pri različnih boleznih. Neurodegenerative diseases encompass a heterogeneous group of neurological disorders characterized by progressive dysfunction and loss of neurons along with the deposition of insoluble protein aggregates. In the doctoral thesis, we investigated the biomarker potential and possible role of tau posttranslational modifications in Alzheimer's disease and other diseases with formerly described pathological tau accumulation. We developed Single Molecule Array assays targeting N-terminal fragments of distinctly phosphorylated tau (p-tau) and evaluated their diagnostic performances in two memory clinic cohorts, including patients along the clinical continuum of Alzheimer’s disease. Cerebrospinal fluid N-terminal p-tau biomarkers were significantly increased in early mild cognitive impairment with no changes in established p-tau biomarker until the dementia stage. Novel p-tau biomarkers distinguished mild cognitive impairment due to Alzheimer’s disease from mild cognitive impairment caused by other conditions significantly better than the established p-tau biomarker. In definite Creutzfeldt-Jakob disease, N-terminal p-tau181, p-tau217 and p-tau231 biomarkers measured in the antemortem cerebrospinal fluid samples had a greater potential to reflect concomitant tauopathies at autopsy. N-terminal p-tau biomarkers were the highest in cases with concomitant Alzheimer's disease, however, they were also increased versus controls in cases without co-pathologies at autopsy. Given the differences in N-terminal p-tau181 and p-tau231 among molecular subtypes of Creutzfeldt-Jakob disease, we hypothesize that N-terminal p-tau biomarkers may also reflect prion-related tau pathology. In multiple sclerosis, N-terminal p-tau biomarkers were significantly increased in patients with primary-progressive compared with relapsing-remitting disease course. An overall correlation of N-terminal p-tau biomarkers with disease duration and clinical rating scale suggested tau phosphorylation status changes with disease severity. In summary, herein-developed biomarkers could facilitate the detection of early tau deposition and will possibly improve our understanding of neurodegenerative processes in studied diseases. fosforiliran tau likvor nevrodegeneracija Alzheimerjeva bolezen Creutzfeldt-Jakobova bolezen multipla skleroza phosphorylated tau cerebrospinal fluid neurodegeneration Alzheimer's disease Creutzfeldt-Jakob disease multiple sclerosis true false false Slovenski jezik Angleški jezik Doktorsko delo/naloga 2024-09-07 07:15:39 2024-09-07 07:15:48 2024-09-10 04:24:03 0000-00-00 00:00:00 2024 0 0 0000-00-00 NiDoloceno NiDoloceno NiDoloceno 0000-00-00 0000-00-00 0000-00-00 1970-01-01 27677 5653.pdf 5653.pdf 1 EA54D89020A73875879AA257352CD02E 6c4ee21db59dc66d52734fc98669d3f545d014e44be6b4987202e07a977295e4 3d180d7b-6cd8-11ef-b232-0050569b8976 https://repozitorij.uni-lj.si/Dokument.php?lang=slv&id=189957 Fakulteta za farmacijo 0 0 0