Diagnostični in prognostični pomen posttranslacijskih sprememb beljakovine tau pri nevrodegenerativnih boleznih

Emeršič, Andreja (author), Čučnik, Saša (mentor)

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.

• Language: Slovenian
• Keywords: fosforiliran tau, likvor, nevrodegeneracija, Alzheimerjeva bolezen, Creutzfeldt-Jakobova bolezen, multipla skleroza
• Work type: Doctoral dissertation
• Organization: FFA - Faculty of Pharmacy
• Year: 2024
• PID: 20.500.12556/RUL-161090
• Publication date in RUL: 07.09.2024

Secondary language

• Language: English
• Title: Diagnostic and prognostic importance of tau protein postranslational modifications in neurodegenerative diseases

Abstract

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.

• Keywords: phosphorylated tau, cerebrospinal fluid, neurodegeneration, Alzheimer's disease, Creutzfeldt-Jakob disease, multiple sclerosis