Funding tool: Basic research projects
Project-ID: LS14-008
Project start: 01. November 2015
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 243.770,00

Brief summary:

A major hallmark of Alzheimer’s disease (AD) is the accumulation of senile plaques containing beta-amyloid (Aß) in the brain. Several lines of evidence suggest that reduced Aß clearance from the brain underlies Aß accumulation. Adenosine triphosphate-binding cassette (ABC) transporters that are expressed in endothelial cells of the blood-brain barrier (BBB) may play an important role in excreting Aß from brain into the blood. A number of studies suggest that P-glycoprotein (ABCB1) function at the BBB may be impaired in AD patients as compared with age-matched control subjects. ABCB1 cooperates closely with another ABC transporter at the BBB, breast cancer resistance protein (ABCG2), in effluxing common substrates from the brain. Given this cooperative action between ABCB1 and ABCG2 and previous data suggesting that ABCG2 may be up-regulated at the BBB of AD patients as possible compensatory mechanism for ABCB1 down-regulation, the role of ABCG2 in AD is currently of high interest. In the present project we will use the non-invasive nuclear imaging method positron emission tomography (PET) to assess for the first time the in vivo function of ABCG2 at the BBB of an AD mouse model (5xFAD) and age-matched wild-type control animals. To complement the in vivo imaging data, in vitro assays will be performed to assess regional ABCG2, ABCB1 and Aß expression in mouse brain. This project will shed light on the role of ABCG2 in AD pathophysiology and provide understanding of the dynamic interplay between ABCG2 and ABCB1 in mediating Aß export from the AD brain. The findings of our project may help to establish ABCG2 as a biomarker for early diagnosis of AD or possibly as a new therapeutic target for treatment of AD.

Keywords:
Neurology, Nuclear Medicine, Preclinical Imaging