Title Alzheimerova bolest: molekularne osnove i terapijski pristup
Author Petra Linić
Mentor Miranda Mladinić Pejatović (mentor)
Committee member Miranda Mladinić Pejatović (predsjednik povjerenstva)
Committee member Ivana Munitić (član povjerenstva)
Committee member Jelena Ban (član povjerenstva)
Granter University of Rijeka (Faculty of Biotechnology and Drug Development) Rijeka
Defense date and country 2017-09-29, Croatia
Scientific / art field, discipline and subdiscipline BIOTECHNICAL SCIENCES Biotechnology
Abstract Alzheimerova bolest (AB) je kronična neurodegenerativna bolest i najčešći oblik senilne
demencije. Najveći poznati rizični čimbenik bolesti je starenje, pa većina pacijenata oboljelih
od Alzheimerove bolesti ima 65 godina starosti ili više. No, ova bolest se ne smatra normalnom
posljedicom starenja, već je rezultat složenih interakcija između više čimbenika uključujući
dob, genetiku, okoliš, način života i koegzistirajuća medicinska stanja. Alzheimerovu bolest
karakterizira progresivno opadanje kognitivnih funkcija, koje obično započinje problemima s
kratkotrajnom memorijom. Bolest se javlja u dva oblika, nasljednom i sporadičnom. Dvije
karakteristične patološke promjene u mozgu koje se javljaju u oba oblika bolesti su odlaganje
amiloidnog β peptida u izvanstanične senilne plakove i nakupljanje abnormalnog
hiperfosforiliranog tau proteina u unutarstanične neurofibrilarne čvorove. Neurodegenerativni
proces AB-i karakterizira sinaptičko oštećenje koje je praćeno gubitkom neurona u cerebralnom
korteksu i određenim subkortikalnim regijama mozga. Oligomerni oblici agregiranog Aβ
toksično djeluju na staničnu i sinaptičku funkciju uzrokujući gubitak neurona i opadanje
kognitivnih funkcija. Ne postoji tretman koji zaustavlja ili preokreće progresiju bolesti, iako
neki mogu privremeno poboljšati simptome. Odobrena terapija AB-i uključuje tri inhibitora
acetilkolinesteraze (donepezil, galantamin i rivastigmin) i jedan antagonist NMDA receptora
(memantin). Tijekom razvoja bolesti oštećuju se kolinergički neuroni, te se inhibicijom enzima
koji razgrađuje acetilkolin nastoji povisiti njegova koncetracija u mozgu. Također, tijekom
bolesti dolazi i do prekomjerne stimulacije NMDA receptora glutamatom što uzrokuje
eksitotoksičnost (oštećenje živčanih stanica zbog prekomjerne stimulacije neurotransmitera), te
se za blokiranje tog učinka koristi antagonist NMDA receptora. Ovi lijekovi privremeno
ublažavaju probleme s pamćenjem i razmišljanjem, ali je njihov klinički učinak skroman.
Tijekom proteklog desetljeća, fokus otkrića novih terapija stavlja se na lijekove koji mijenjaju
tijek bolesti. Cilj takvih lijekova je usporiti progresiju neurodegenerativnog procesa
inhibiranjem kritičnih događaja u patofiziologiji bolesti, koji uključuju taloženje izvanstaničnih
senilnih plakova i unutarstaničnih neurofibrilarnih čvorova. Međutim, nakon desetljeća
istraživanja, Alzheimerova bolest je i dalje neizlječiva i time se smatra jednim od glavnih
ljudskih zdravstvenih izazova.
Abstract (english) Alzheimer's is a chronic neurodegenerative disease and the most common form of senile
dementia. The greatest known risk factor of the disease is aging, so most patients with the
disease are 65 years of age or older. However, it is not considered a normal part of aging, but
the result of complex interactions among many factors including age, genetics, environment,
lifestyle, and coexisting medical conditions. Alzheimer's disease is characterized by a
progressive decline in cognitive function, which usually begins with problems with short-term
memory. The disease occurs in two forms, hereditary and sporadic. Two characteristic
pathological changes in the brain that occur in both forms of disease are the accumulation of
amyloid β peptide in extracellular senile plaques and the accumulation of abnormal
hyperphosphorylated tau protein in the intracellular neurofibrillary tangles. The
neurodegenerative process of the disease is characterized by a synaptic damage which is
accompanied by the loss of neurons in the cerebral cortex and certain subcortical regions of the
brain. Aggregated oligomeric forms of Aβ have toxic effects to the cellular and synaptic
function, causing loss of neurons and decline in cognitive function. There is no treatment that
stops or reverses the progression of the disease, although some may temporarily improve the
symptoms. Approved therapy includes three inhibitors of acetylcholinesterase (donepezil,
galantamine and rivastigmine) and one NMDA receptor antagonist (memantin). During the
development of the disease cholinergic neurons are damaged, and the inhibition of the enzyme
disintegrating acetylcholine aims to increase its concentration in the brain. Likewise, during the
disease, excessive stimulation of NMDA receptor by glutamate causes excitotoxicity (nerve
cells are damaged by excessive stimulation by neurotransmitters), therefore NMDA receptor
antagonist is used to block this effect. These medications temporarily reduce memory and
thinking problems, but their clinical effect is modest. Over the past decade, the focus of
discovery of new therapies is on medicines that change the course of the disease. The aim of
such drugs is to slow down the progression of the neurodegenerative process by inhibiting
critical events in the pathophysiology of the disease, including the deposition of extracellular
senile plaques and intracellular neurofibrillary tangles. However, after decades of research,
Alzheimer's disease is still incurable and is considered to be one of the major human health
challenges.
Keywords
Alzheimerova bolest
terapija
antagonist NMDA receptora
inhibitori acetilkolinesteraze
Language croatian
URN:NBN urn:nbn:hr:193:997558
Study programme Title: Biotechnology and drug research Study programme type: university Study level: undergraduate Academic / professional title: sveučilišni/a prvostupnik/prvostupnica biotehnologije i istraživanja lijekova (sveučilišni/a prvostupnik/prvostupnica biotehnologije i istraživanja lijekova)
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Created on 2017-11-03 09:21:47