Tilbake til søkeresultatene

JPND-EU Joint Programme - Neurodege

PET analyses of ABC transporter function for diagnostics and stratification of dementia patients

Alternativ tittel: New functional analyses for patients with dementia Nye funktionelle analyser for demenspasienter

Tildelt: kr 6,5 mill.

Tidlig og spesifikk diagnosestilling av demenspasienter er vanskelig. I 2010 har vi funnet ett nytt gen som er ansvarlig for transportfunksjonen i blod-hjerne skranken (www.pahnkelab.eu). Genet ABCC1 er ansvarlig for å utskille Abeta fra hjernen og er ødelagt eller nedsatt i funksjonen når pasienter utvikler Alzheimer demens. Vi har utviklet nye metoder for å måle ABCC1 funksjonen, bl.a. en metode som benytter radioaktive stoffer for å bestemme aktiviteten av transporteren i blod-hjerne skranken i musemodeller. I det planlagte internasjonale prosjektet skal vi etablere metoden for mennesker sånn at den kan benyttes for å bestemme pasienter som kunne behandles med ABCC1 aktivatorer. I tillegg skal vi utvikle ligne metoder for ABCA7. Både ABCC1 og ABCA7 er risikofaktorer for demensutvikling når funksjonen er nedsatt. PETABC konsortium består av partner fra Norge (koordinator), Sverige, Latvia, Tyskland, Frankrike, Østerrike og Tsjekkia.

The blood-brain barrier (BBB) expresses different ATP-binding cassette (ABC) transporters, which control the access of endogenous and exogenous compounds from the blood into the brain as well as their removal from the brain into the blood. The export function of the BBB is of increasing importance and is moving continuously into the focus of research on neurodegenerative diseases (ND). We have described for the first time that the ABC transporter C1 (ABCC1) is exceptionally important for the export of metabolites from the brain, especially for amyloid-ß (Aß). In 2019, the first ABCC1 mutation was found in a family from Phoenix (USA) with inherited clinical Fronto-temporal Lobe Degeneration (FTD) and histological AD unpublished data. Apart from ABCC1, several other ABC transporters have been linked to NDs. Amongst them, a potential role of ABCA7 has been discovered in a large genome-wide association study. We hypothesized that ABC transporter function can be used to determine the impairment and remaining capacity of the BBB export in individual patients in vivo with different NDs (AD, PD, LBD, PSP). Moreover, ABC transporters may be therapeutically targeted to enhance the Aß export capacity of the BBB. To this end, we performed the drainAD phase IIa study (NCT03417986) to investigate the potential role of ABCC1 as a new diagnostic and treatment target for AD. The study showed that patients and controls excrete Aß40 and Aß42 in a time-dependent manner, presumably according to their BBB ABCC1 function. To further advance this novel therapeutic concept, methodology is critically needed to directly measure cerebral ABCC1 function in vivo in patients. Over the last years, partners of this consortium have performed multiple in vitro and functional animal studies in vivo to describe the function of ABCC1 and ABCA7, and have established a new positron emission tomography (PET) protocol to measure ABCC1 function in the rodent brain, which potentially can be used in patients.

Publikasjoner hentet fra Cristin

Ingen publikasjoner funnet

Ingen publikasjoner funnet

Ingen publikasjoner funnet

Ingen publikasjoner funnet

Budsjettformål:

JPND-EU Joint Programme - Neurodege

Finansieringskilder