Doprinos poremećaja krvno-moždane barijere patofiziologiji Alchajmerove bolesti u transgenim animalnim modelima

Abstract

Krvno-moždana barijera (KMB) je ključna strukturna i funkcionalna prilagođenost krvnih sudova u centralnom nervnom sistemu, neophodna za njegovo normalno funkcionisanje. Osnovni zadatak KMB je da spreči slobodan prolazak humoralnih i hemijskih faktora i ćelija iz krvi u moždani parenhim i obrnuto. Periciti su ćelije koje naležu na endotelne ćelije krvnih kapilara, i zajedno sa endotelnim ćelijama, kao i proširenjima astrocitnih nastavaka i bazalnom membranom, čine KMB. Periciti, osim uloge u svim aspektima funkcionisanja i propustljivosti KMB, imaju ulogu u regulaciji protoka krvi, angiogeneze, čišćenja toksičnih materija iz mozga, neuroinflamaciji, kontrolišu ekspresiju proteina poreklom iz endotelnih ćelija koji ulaze u sastav adherentnih i čvrstih veza endotelnog sloja, a opisana su i njihova svojstva slična nervnim matičnim ćelijama. Alchajmerova bolest (AB) je neurodegenerativno oboljenje i najčešći oblik demencije kod ljudi starijih od 65 godina. AB se na neuropatološkom nalazu karakteriše akumulacijom vanćelijskog amiloida β i unutarćelijskog tau proteina u moždanom tkivu, kao i gubitkom neurona. Dodatno, istraživanja su pokazala da se promene u moždanoj cirkulaciji, protoku krvi i propustljivosti kapilara mogu primetiti i pre pojave kliničke slike sporadičnog oblika AB. Cilj ove teze je bio da se ispita integritet KMB i uloga percita u prisustvu i odsustvu AB patologije. Dodatni cilj je bio i da se ispita uloga PICALM proteina, jer se pokazalo da mutacije u ne-kodirajućem regionu PICALM gena mogu da predstavljaju faktor rizika za razvoj AB u kasnijem dobu (eng. late-onset). Uloga PICALM-a je praćena zasebno na endotelnim ćelijama i neuronima, a ispitana je i posledica farmakološkog povećanja ekspresije PICALM-a na nivo amiloida β. Konačno, ispitana je dijetalna restrikcija kao potencijalna intervencija u cilju smanjenja patologije vezane za AB...

The blood-brain barrier (BBB) is a key structural and functional adaptation of blood vessels in the central nervous system, necessary for its normal functioning. The basic task of BBB is to prevent the free passage of humoral and chemical factors and cells from the blood into the brain parenchyma and vice versa. Pericytes are cells that attach to the endothelial cells of the blood capillaries, and together with the endothelial cells, as well as astrocytic end-feet and the basement membrane, constitute BBB. Pericytes, in addition to their role in all aspects of the functioning and permeability of BBB, play a role in regulation of blood flow, angiogenesis, clearance of toxic substances from the brain, neuroinflammation, control the expression of various proteins in endothelial cells, especially adherent and tight junctions proteins of the endothelial layer, and their properties similar to nerve stem cells are also described. Alzheimer's disease (AD) is a neurodegenerative disease and the most common form of dementia in people over 65 years of age. AD on neuropathological findings is characterized by accumulation of extracellular amyloid β and intracellular tau protein in brain tissue, as well as neuronal loss. In addition, studies have shown that changes in cerebral circulation, blood flow, and capillary permeability can be observed even before the onset of clinical presentation of sporadic AD. The aim of this thesis was to investigate the integrity of BBB and the role of pericytes in the presence and absence of AD pathology. Additional aim was to investigate the role of PICALM proteins, as it has been shown that mutations in the non-coding region of the PICALM gene may represent a risk factor for the development of late-onset AD. The role of PICALM was studied separately on endothelial cells and neurons, and the consequence of the pharmacological increase in PICALM expression to amyloid β levels was examined...