The role of chaperones in development and treatment of Alzheimer's disease

Alzheimerova bolest je progresivni neurodegenerativni poremećaj uzrokovan akumulacijom i agregacijom β-amiloidnih peptida koja rezultira brojnim toksičnim čimbenicima poput neurofilamentnih zapleta hiperfosforiliranog proteina tau, povećanog stupnja nastajanja reaktivnih kisikovih vrsta, kroničnog upalnog odgovora, ionske neravnoteže i u konačnici apoptoze neurona te prekid sinaptičkih veza što uzrokuje demenciju. Budući da ova bolest u svojoj osnovi sadrži poremećaje u staničnoj proteostazi i metabolizmu proteina, kao važan čimbenik njezine patofiziologije pokazali su se šaperoni. To su proteini koji sudjeluju u brojim staničnim procesima poput smatanja novosintetiziranih i nepravilno smotanih proteina, translokacije proteina preko membrane, razmatanja makromolekulskih agregata i aktivacije brojnih enzima te receptora čime na nezamjenjiv način reguliraju staničnu proteostazu. U zadnjih nekoliko godina utvrđene su uloge različitih šaperonskih obitelji u sprječavanju, ali i pogodovanju agregacije β-amiloida i proteina tau, modulaciji imunosnog odgovora i smanjenju oksidativnog stresa stanice te direktnom sprječavanju apoptoze neurona. Iz ovog razloga sve više strategija liječenja Alzheimerove bolesti temelji se na modulaciji šaperonskog sustava što bi moglo predstavljati velik korak u liječenju ove, ali i drugih neurodegenerativnih bolesti. Ipak, preduvjet za uspješnost takvih istraživanja je razlučivanje mehanizama šaperonskih sustava u kontekstu šaperonske mreže što bi odgonetnulo detaljniju ulogu ovakvih sustava u navedenim bolestima čime bi se otvorile nove perspektive njihova liječenja.Alzheimer's disease is a progressive neurodegenerative disorder caused by abnormal accumulation and aggregation of amyloid-β peptide which results in various toxic effects such as neurofibrillary tangles of hyperphosphorilated tau protein, increased concentration of reactive oxygen species, chronic inflammation and ionic disequilibrium, all of which ultimately lead to neuronal apoptosis and loss of synapses, thus causing dementia. The most important element of this disease is a disruption of cell proteostasis which is why molecular chaperones have shown to be one of the main factors in its pathophisiology. Molecular chaperones are proteins that are involved in many cellular events such as folding of newly synthesized and/or unfolded proteins, membrane translocation of macromolecules, unfolding of protein aggregates and maintining the function of many enzymes and receptors. Recently, many functions of chaperones in prevention and amelioration of the aggregation of amyloid proteins have been found. Furthermore, their role has been recognized in modulating the immune system, in reducing the concentration of reactive oxygen species and in preventing cell apoptosis directly. This is why many of new strategies of treating Alzheimer's disease are based on modulating the chaperone systems which could be a big step in curing this and many other neurodegenerative diseases. For these strategies to succeed, intensive research regarding mechanisms of chaperone function in the context of the chaperone network will have to be conducted. This would reveal a detailed role of these systems in Alzheimer's and other neurodegenerative diseases