PET imaging to assess blood-brain barrier function in alzheimers disease

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A major hallmark of Alzheimer¿s disease (AD) is the accumulation of senile plaques containing beta-amyloid in the brain. Several lines of evidence suggest that reduced Abeta clearance from the brain underlies Abeta accumulation. Adenosine triphosphate (ATP)-binding cassette (ABC) transporters that are expressed in endothelial cells of the blood-brain barrier (BBB) may play an important role in excreting Abeta 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. Our own data obtained in amyloid precursor protein (APP) transgenic mice (APPtg) that lack the multidrug resistance protein 1 (ABCC1; APPtg x ABCC1-/-) suggest that ABCC1 may play a more important role than ABCB1 in mediating Abeta clearance from the brain as reflected by up to 14-fold increased Abeta levels in brains of APPtg x ABCC1-/- mice as compared with control mice expressing ABCC1. Moreover, chronic treatment of APPtg mice with thiethylperazine, an antiemetic drug which activates ABCC1 transport activity in vitro, resulted in significant reductions in Abeta load as compared with untreated control animals. However, so far it is not known if ABCC1 function at the BBB is indeed altered during the progression of AD and if treatment with thiethylperazine indeed increases the function of ABCC1 at the BBB. To answer these important questions we will directly measure the functional activity of ABCC1 in vivo at the BBB of AD mouse models using positron emission tomography (PET) and the newly developed radiotracer [18F]BFEP. In addition, Abeta load in mouse brains will be assessed with [11C] Pittsburgh compound B ([11C] PIB) to establish a correlation between regional ABCC1 function and Abeta load in brains of APPtg mice. Using this experimental approach we will investigate the time course of ABCC1 function decline in AD mouse brain and study the effect of thiethylperazine treatment on ABCC1 function. In vivo PET experiments will be complemented with comprehensive immunohistochemistry (IHC) analyses of pathological markers, ABCC1 and Abeta as well as Western blot analysis. We hypothesize that ABCC1 function is decreased in AD mice and that there is an inverse relationship between regional brain Abeta load and ABCC1 function. Pharmacological induction of ABCC1 activity at the BBB may represent an interesting future therapeutic strategy in AD and PET imaging of cerebral ABCC1 function may be a very useful imaging biomarker in the development of such new therapeutics as well as in early diagnosis of AD.