Developmental mechanisms of Alzheimer’s disease

Abstract

Alzheimerova bolest je kronična neurodegenerativna bolest s dobro definiranim patofiziološkim mehanizmima koji najčešće utječu na područja medijalnog temporalnog režnja i susjedne neokortikalne strukture. Ekstracelularni neuralni plakovi i inercelularni fibrili su najpoznatije patološke značajke Alzheimerove bolesti, a nastaju zbog akumulacije amiloid β peptida i citoskeletnih promjena koje proizlaze iz hiperfosforilacije i agregacije mikrotubul vezujućeg tau proteina. Nakon originalno uspostavljene amiloidne teroije prema kojoj je amiloid β bio glavni nositelj patologije AD istraživanjima je utvrđeno da tau protein svojom agregacijom u oligomere i fibrile uvelike doprinosi progresiji same bolesti. Unatoč brojnim istraživanjima patologije AD i dalje ostaje nepoznato zašto razvoj bolesti traje desetljećima prije pojave prvih simptoma, no smatra se da bi tome mogao biti razlog smanjena sposobnost uklanjanja pogrešno smotanih, oligomernih i agregiranih oblika tau proteina koji se nakupljaju starenjem. Nakon neuspješnih terapijskih intervencija usmjerenih na amiloid β noviji lijekovi za cilj imaju fosforilaciju i agregaciju tau proteina, te se još čekaju ishodi njihovih kliničkih studija. Također od velike važnosti za projektiranje novih terapeutika je i točno razumijevanje mehanizama kojima se toksični tau oligomeri šire kroz sinapsu.Alzheimer's disease is a chronic neurodegenerative disease with well-defined pathophysiological mechanisms that most often affect the medial temporal lobe and adjacent neocortical structures. Extracellular neural plaques and intercellular fibrils are most common pathological features of Alzheimer's disease, resulting from the accumulation of amyloid β peptides and cytoskeletal changes resulting from hyperphosphorylation and aggregation of microtubule binding tau protein. After the originally established amyloid theory according to which amyloid β was the main bearer of AD pathology, was found that tau protein by its aggregation into oligomers and fibrils greatly contributes to the progression of the disease as well. Despite the numerous studies of AD pathology, it remains unknown why the development of the disease lasts decades before the appearance of the first symptoms, but it is considered that the reason could be diminished ability to remove misfolded, oligomeric and aggregated forms of protein, which accumulate with age. Following unsuccessful therapeutic interventions that target amyloid β, new drugs are aiming at phosphorylation and aggregation of tau protein but we are still awaiting the outcomes of their clinical studies. In addition, the accurate understanding of the mechanisms by which the toxic tau oligomers are spread through the synapse is of great importance for the design of new therapies