Temporal analysis of microglial morphology in mice expressing human Tau with a P301S mutation

Daan Verhaege
Tijdens het thesisonderzoek maakten we gebruik van hTau.P301S muizen. Deze muizen expressen humaan Tau met een P301S mutatie, waardoor Tau-klonters gevormd worden binnenin zenuwcellen en de muizen dementiestoornissen ontwikkelen. In die muizen hebben we een temporele analyse gemaakt van microglia en diens functie.

Maak kennis met de cellen die dementie eten!

Wanneer je eender welke persoon met dementie op dit moment zou vragen wat ‘microglia’ zijn, krijg je vast geen zinnig antwoord te horen. Nochtans zou dit volgens wetenschappers van de Universiteit Gent en de Vrije Universiteit van Amsterdam spoedig kunnen veranderen. Hun recent onderzoek toont aan dat microgliale cellen een rol spelen in de progressie van dementie en deze dus beter niet vergeten worden als potentieel therapeutisch doelwit.

Over zenuwen en eiwitklonters

De meeste hersenaandoeningen zijn het gevolg van het afsterven van zenuwcellen. De ziekte van Alzheimer bijvoorbeeld, wordt gekenmerkt door de dood van zenuwcellen gelegen in de hypothalamus (het hersengebied verantwoordelijk voor het geheugen) waardoor mensen met Alzheimer al gauw geheugenstoornissen ontwikkelen. De meest bekende oorzaken van zenuwceldood zijn zuurstoftekort en ontstekingen. Recent werd door onderzoekers echter een nieuwe oorzaak gevonden: de vorming van grote eiwitklonters in de zenuwen. Het ‘tau-eiwit’ bijvoorbeeld, helpt de cel zijn vorm te behouden door het verstevigen van het celskelet. Onder bepaalde omstandigheden kan het tau-eiwit echter ook andere tau-eiwitten binden en kunnen tau-klonters zich vormen binnen zenuwcellen. Deze klonters lijken erg op klitten (‘tangles’ in het Engels) en worden door wetenschappers ook wel ‘neurofibrilary tangles’ genoemd, kortweg ‘NFTs’.

Van tau tot tauopathie

De mechanismen van hoe NFTs ontstaan, zich verspreiden doorheen de hersenen en zenuwceldood veroorzaken worden collectief ‘tauopathie’ genoemd. Tauopathie blijkt een belangrijke speler te zijn in vele dementietypes zoals Alzheimer, maar ook de minder bekende frontotemporale dementie. Die laatste kan veroorzaakt worden door mutaties (dit zijn wijzigingen) in het stukje DNA dat informatie bevat om het eiwit tau te maken. Die mutaties zorgen ervoor dat het tau-eiwit plots nog beter kan binden aan andere tau-eiwitten, waardoor al snel een tau-klonter ontstaat en dus NFTs gevormd worden binnen zenuwcellen. Waarom die cellen dan sterven en hoe dat fenomeen zich verspreidt doorheen de hersenen zijn vragen die wetenschappers momenteel proberen te beantwoorden.

Demente muizen?

Onderzoek naar de mechanismen van tauopathie bij dementie wordt bemoeilijkt door de schaarsheid van hersenstaaltjes, die overigens enkel te verkrijgen zijn na het overlijden van de patiënt. In de biotechnologie hebben ze hier een aardig trucje voor gevonden: transgene muizen. Het stukje DNA dat informatie bevat over het tau-eiwit (al dan niet met de ziekteverwekkende mutatie) wordt gewoon bij de muis ingebracht. Muizen gemaakt op die manier worden dan ook gekenmerkt door de vorming van NFTs binnen zenuwcellen en vertonen symptomen van dementie. Die transgene muizen kunnen dan gebruikt worden voor onderzoek naar tauopathie en de zoektocht naar de oorzaak van en mogelijks ook medicatie tegen Alzheimer en frontotemporale dementie. In de huidige studie maakten we gebruik van hTau.P301S muizen, wat de wetenschappelijke naam is van muisjes die het humane DNA bevatten voor het tau-eiwit (hTau) met een specifieke mutatie (P301S). De muizen (hierna demente muizen) werden zo gemaakt dat ze het humane mutante tau enkel aanmaken binnen zenuwcellen en zo dementieverschijnselen ontwikkelen. Op die manier kan ongestoord de rol van andere onveranderde cellen (zoals immuuncellen) in tauopathie bestudeerd worden.

Kleine cellen, grote eetlust

Microglia zijn kleine immuuncellen in de hersenen die hun omgeving aftasten met behulp van lange uitlopers of vertakkingen. Als ze ziekteverwekkers vinden, verwijderen ze die onder andere door het slechte goedje simpelweg op te eten in een proces dat wetenschappers ‘fagocytose’ noemen. Onlangs hebben onderzoekers verondersteld dat microglia mogelijks een rol spelen in tauopathie, maar of ze gunstig of schadelijk zijn is nog onbekend. In onze huidige studie (uitgevoerd aan de Universiteit Gent en de Vrije Universiteit Amsterdam) onderzochten we hoe de microglia vertakkingen veranderen in reactie op de aanwezigheid van NFTs. Daarnaast onderzochten we of microglia in staat zijn om tau-klonters te fagocyteren.

Microglia ‘voelen’ tau-klonters

Om deze onderzoeksvragen na te gaan, gebruikten we normale en demente muizen. De hersenen van deze muizen werden geïsoleerd, in dunne plakjes gesneden en met een microscoop onderzocht. Normale muizen vertoonden microglia met veel en dunne vertakkingen, typerend voor gezonde en rustende microglia. Gedementeerde muizen daarentegen bevatten microglia met kortere en dikkere vertakkingen. Dit zijn kenmerken van ‘geactiveerde’ microglia. Deze observaties wijzen erop dat microglia op nog onbekende wijze reageren op zenuwcellen met tau-klonters en hierdoor actiever worden.

De figuur toont twee types/vormen van microglia. Gezonde/rustende microglia hebben veel dunne en sterk vertakte uitlopers. Geactiveerde microglia hebben dikkere en minder vertakte uitlopers.

Microglia lusten tau!

Wanneer microglia ziekteverwekkers eten, dan komen deze terecht in de maag van de cel die bestaat uit zakachtige structuren die ‘lysosomen’ worden genoemd. In ons huidig onderzoek zagen we de lysosomen opzwellen in de microglia van gedementeerde muizen, wat suggereert dat deze cellen actief aan het eten zijn. Binnenin deze grotere lysosomen in gedementeerde microglia detecteerden we kleine hoeveelheden tau-eiwit, wat aangeeft dat microglia (aanwezig in de hersenen van demente muizen) tau-klonters proberen op te eten! Wat er hierna gebeurt met de opgegeten tau-klonters, weten we niet zeker. Momenteel zijn er twee theorieën die mogelijk lijken. Een eerste mogelijkheid is dat microglia deze tau-klonters transporteren naar andere plaatsen om ze daar terug vrij te geven en zo het probleem te verspreiden doorheen de hersenen. Het therapeutisch remmen van deze transportfunctie zou de progressie van dementie kunnen vertragen. Een tweede theorie stelt dat microglia het tau opeten en verteren in hun maag. Dit laatste zou betekenen dat microglia de opstapeling van tau-klonters in zenuwcellen kunnen remmen wanneer we microglia therapeutisch stimuleren om hier meer van te eten.

De figuur toont twee cellen. Een zenuwcel is weergegeven samen met tau-klonters die opbouwen binnenin de cel. Hiernaast is een microgliale cel weergegeven. Deze laatste bevat tau-klonters in diens maag (bestaande uit zakachtige structuren of lysosomen).

Een hoopvolle blik vooruit

De voorlopige conclusie van ons onderzoek: microglia reageren op de aanwezigheid van tau-klonters in zenuwcellen, nemen een geactiveerde vorm aan en kunnen deze klonters zelfs opeten. Hoewel er nog bijkomend onderzoek nodig is, blijkt nu al dat de rol van deze kleine cellen potentieel grote gevolgen kan hebben op het leven van miljoenen mensen met dementie.

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Universiteit of Hogeschool
Biochemistry & biotechnology. Major: Biomedical sciences. Minor: Neurosciences
Publicatiejaar
2018
Promotor(en)
Prof. Elga De Vries (Vrije Universiteit Amsterdam), Prof. Roosmarijn Vandenbroucke (Universiteit Gent)