Alzheimerova bolest: molekularne osnove i terapijski pristup

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.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