Povezanost sastava gangliozida i izražaja neuroplastina s neurodegenerativnim promjenama [Association of ganglioside composition and neuroplastin expression with neurodegenerative changes]

Ilić, Katarina (2018) Povezanost sastava gangliozida i izražaja neuroplastina s neurodegenerativnim promjenama [Association of ganglioside composition and neuroplastin expression with neurodegenerative changes]. PhD thesis, Sveučilište u Zagrebu.

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Abstract

Neuroplastin is a highly glycosylated transmembrane protein whose membrane positioning is dependent on membrane ganglioside composition. In this thesis, we investigated changes of neuroplastin expression in neurodegeneration. In human hippocampal tissue affected by sporadic Alzheimer's disease (AD), we show that neuroplastin immunoreactivity pattern is similar to control pattern, namely in cell bodies and dendrites of glutamatergic neurons of the trisynaptic pathway. Neuroplastin immunoreactivity is highly increased in AD, particularly in the dentate gyrus and subiculum in early stages of the disease. In a transgenic mouse model of familial AD, neuroplastin and plasma membrane calcium ATP-ase expression are decreased in cortex and hippocampus when compared to wild-type mice. This finding may be attributed to changed molecular mechanisms of learning and memory disorder. Neuroplastin expression and its positioning within membrane domains is highly dependent on ganglioside composition and thus directly affected when membrane ganglioside composition is altered, as shown by analysis of isolated membrane fractions derived from brain tissue of different mice models with aberrant ganglioside synthesis. In vitro studies showed that GM1, a complex a-series ganglioside, predominantly co-localizes with neuroplastin and is probably responsible for its positioning within lipid rafts. Based on joined data of already described alterations of membrane domains in neurodegeneration and here presented association of expression and membrane positioning of neuroplastin with ganglioside composition, we conclude that neuropathological cascade in Alzheimer’s disease affects cell-adhesion molecule neuroplastin. Changed neuroplastin expression leads to altered cell calcium signaling and inability to maintain learning and memory molecular mechanisms.

Abstract in Croatian

Neuroplastin je glikozilirani transmembranski protein čije pozicioniranje u membrani ovisi o njezinom gangliozidnom sastavu. U ovoj disertaciji istražene su promjene neuroplastina u neurodegeneraciji. U uzorcima ljudskog hipokampusa zahvadenima sporadičnom Alzheimerovom patologijom pokazano je da je uzorak ekspresije neuroplastina jednak kontrolnome, odnosno da se nalazi u membranama i dendritima glutamatergičnih neurona trisinaptičkog puta, ali je izražaj značajno povedan, pogotovo u regijama girusa dentatusa i subikuluma u ranoj fazi bolesti. U mišjem transgeničnom modelu nasljedne Alzheimerove bolesti izražaj neuroplastina, i s njim povezane kalcijske ATP-aze, je manji u kori velikog mozga i hipokampusu u odnosu na divlji tip, što može predstavljati molekularnu podlogu poremedaja mehanizama pamdenja. Izražaj neuroplastina i njegovo pozicioniranje unutar membranskih domena izravno ovisi o promijenjenom gangliozidnom sastavu membrane što pokazuju rezultati analize izoliranih membranskih frakcija moždanog tkiva različitih mišjih modela s poremedenom sintezom i sastavom gangliozida. Istraživanje in vitro je pokazalo da GM1, kompleksni gangliozid a-serije, u najvedoj mjeri kolokalizira s neuroplastinom i najvjerojatnije je odgovoran za njegovo pozicioniranje unutar lipidnih splavi. Zbog do sada opisanih promjena membranskih domena u neurodegeneraciji, te u ovoj disertaciji razjašnjenog uvjetovanja izražaja i membranske pozicije neuroplastina o gangliozidima, zaključujemo da neuropatološka kaskada Alzheimerove bolesti zahvada i molekulu stanične adhezije neuroplastin. Promjene ekspresije neuroplastina dovode do poremedene stanične signalizacije ovisne o kalcijevim ionima i nemogudnosti održavanja molekularnih mehanizama odgovornih za učenje i pamdenje.

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