Doprinos poremećaja krvno-moždane barijere patofiziologiji Alchajmerove bolesti u transgenim animalnim modelima
Contribution of blood-brain barrier disruption to the pathophysiology of Alzheimer's disease in transgenic animal models
Author
Lazić, DivnaMentor
Kanazir, SelmaCommittee members
Perović, MilkaNedeljković, Nadežda
Kanazir, Selma
Perović, Milka
Metadata
Show full item recordAbstract
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 k...arakteriše
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...