Uloga crijevne mikrobiote i prehrane u patogenezi Alzheimerove bolesti

undergraduate thesis

• Title (english): Role of gut microbiota and nutrition in pathogenesis of Alzheimer disease
• Author: Klara Martinović
• Mentor: Nada Oršolić (mentor)
• Granter: University of Zagreb; Faculty of Science; (Department of Biology); Zagreb
• Defense date and country: 2020, Croatia
• Scientific / art field, discipline and subdiscipline: NATURAL SCIENCES; Biology

Abstract

Sastav crijevne mikrobiote varira kod svakog pojedinca, a ovisan je prehrani, starosti, okolišnimčimbenicima i sveukupnom načinu života. Disbioza crijevne mikrobiote doprinosi razvoju mnogih bolesti među kojima je i Alzheimerova bolest (AB). Alzheimerova bolest je neurodegenerativna bolest koju karakterizira taloženje β-amiloidnih (Aβ) plakova i neurofibrilarnih čvorova (NFTs). Za stvaranje Aβ koji su skloni agregiranju zaslužno je cijepanje amiloid prekursorskog proteina (APP) β- i... More γ-sekretazom, dok agregaciju tau protena u NFTs potiču posttranslacijske modifikacije poput fosforilacije. Ključni patogeni mehanizmi AB-a su oksidacijski stres i neuroupala koje prati aktivacija mikroglija stanica i astrocita. Oksidacijski stres predstavlja stanje povećane koncentracije oksidansa koji oštećuju stanice i potiču signalizaciju za apoptozu. Aktivirane mikroglija, astrociti i sustav komplementa okružuju nataložene Aβ plakove i NFTs što uzrokuje neuroupalu, proces koji zbog povećane permeabilnosti krvno-moždane barijere (BBB) može biti potaknut proupalnim citokinima u mozgu. U fiziološkim uvijetima mikroglija stanice imunosnim odgovorom uklanjaju Aβ, no taj se proces pod utjecajem starenja i promjene sastava crijevne mikrobiote mijenja pa dolazi do progresivnog taloženja Aβ. Za razvoj AB-a s kasnim početkom rizik predstavljaju genetički faktori, a posebice alel ε4 apolipoproteina E. APOE4 ima najveći afinitet za vezanje Aβ pa tako potiče formiranje plakova. Crijevna mikrobiota utječe na signalizaciju u mozgu putem dvosmjerne komunikacije koja se naziva os crijeva-mozak kojom putuju neuromodulatori kao što su kratkolančane masne kiseline (SCFA) koje proizvode bakterije. Za SCFAs je poznato da imaju protuupalne učinke i održavaju cjelovitost crijevne barijere koja predstavlja fizičku barijeru između mikrobioma crijeva i imunosnog sustava domaćina. Osim crijevne i krvno-moždana barijera štiti od ulaska molekula i patogena u mozak, ali i posreduje dotok Aβ pa se njenim narušavanjem potiče patogeneza AB-a. Bakterijski amiloidi u crijevima mogu izazvati imunosni odgovor na endogeno proizvedene Aβ u mozgu što zbog povećanja količine proupalnih citokina uzrokuje neuroupalu. Prehrana predstavlja glavni čimbenik koji određuje sastav crijevne mikrobiote čime indirektno utječe na patogenezu AB-a, ali tvari poput polifenola iz namirnica biljnog podrijetla imaju direktan učinak na inhibiciju agregacije i uklanjanje Aβ te signaliziraju za autofagiju i redukciju upale. Najbolji primjer povoljnog utjecaja prehrane za prevenciju bolesti poput AB-a je mediteranski tip prehrane sa ekstradjevičaniskim maslinovim uljem koje sadrži važne fenole i djeluje antioksidacijski. Sastav crijevne mikrobiote pa tako i razina proupalnih citokina može biti regulirana i probioticima i tako pozitivno utjecati na neuroupalu i kognitivne funkcije. Less

Abstract (english)

The composition of gut microbiota varies from individual to individual and depends on diet, environmental factors, and the overall lifestyle. Dysbiosis of gut microbiota contributes to the development of many diseases, one of which is the Alzheimer disease (AD). Alzheimer’s disease is a neurodegenerative disease characterized by the deposition of β-amyloid plaques and neurofibrillary tangles (NFTs). The amyloid precursor protein (APP) cleavage by β- and γ-secretase is responsible... More for the formation of Aβs that are prone to aggregation, while the aggregation of tau proteins in NFTs is stimulated by posttranslational modifications such as phosphorylation. The key pathogenic mechanisms of AD are oxidative stress and neuroinflammation which are followed by the activation of microglia cells and astrocytes. Oxidative stress is a condition of increased concentration of oxidants that damage cells and stimulate signalization for apoptosis. Activated microglia, astrocytes and the complement system surround deposited Aβ plaques and NFTs which causes neuroinflammation, a process that can be triggered by proinflammatory cytokines in the brain due to increased permeability of the blood-brain barrier (BBB). Under physiological conditions, microglia cells remove Aβ through immune response; but this process changes due to ageing and changes in the composition of gut microbiota, resulting in progressive deposition of Aβ. Genetic factors, especially the ε4 allele of the apolipoprotein E, pose a risk for the development of AB with a late onset. APOE4 has the highest affinity for Aβ binding, thus stimulating plaque formation. Gut microbiota affects brain signalization via bidirectional communication called gut-brain axis, through which neuromodulators travel, such as short-chain fatty acids (SCFAs) produced by bacteria. SCFAs are known to have anti-inflammatory effects and maintain the integrity of the gut barrier which represents a physical barrier between the gut microbiome and the host immune system. Apart from the gut barrier, the blood-brain barrier also protects against the entry of molecules and pathogens into the brain, but also mediates the influx of Aβ so its disruption stimulates the pathogenesis of AB. Bacterial amyloids in the guts can cause an immune response to endogenously produced Aβ in the brain, which, due to an increase in the amount of proinflammatory cytokines causes neuroinflammation. Nutrition is the main factor that determines the composition of gut microbiota which indirectly affects the pathogenesis of AD; yet substances such as polyphenols from foods of plant origin have a direct effect on the inhibition of aggregation and removal of Aβ. They also play a role in the signalization for autophagy and in inflammation reduction. The best example of a diet which can prevent diseases such as AD is the Mediterranean type of diet with extra-virgin olive oil which contains important phenols and has an antioxidative effect. The composition of gut microbiota, as well as the level of proinflammatory cytokines, can be regulated by probiotics which can positively affect neuroinflammation and cognitive functions. Less

• Keywords: Alzheimerova bolest
• Language: croatian
• URN:NBN: urn:nbn:hr:217:064577
• Study programme: Title: Molecular Biology; Study programme type: university; Study level: undergraduate; Academic / professional title: sveučilišni/a prvostupnik/prvostupnica (baccalaureus/baccalaurea) molekularne biologije (sveučilišni/a prvostupnik/prvostupnica (baccalaureus/baccalaurea) molekularne biologije)
• Type of resource: Text
• File origin: Born digital
• Access conditions: Open access
• Created on: 2020-09-03 11:52:29