The role of the blood-brain barrier in Alzheimer s disease: Interaction of LRP1 and ABC transporter function

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It has been known for a long time that the accumulation of the neurotoxic beta-amyloid peptides (Aβ) is a characteristic hallmark of Alzheimer’s disease (AD). Dr. Randy Bateman and others demonstrated that the production rate of Aβ peptides does not differ between healthy individuals and patients with AD. We and others have shown the clearance function of Aβ peptides between healthy and demented individuals is dramatically altered. Therefore, we propose in this application to further clarify the details of this clearance mechanisms of the largest Aβ disposal structure of the brain, the blood brain barrier (BBB). We have already shown that LRP1, ABC transporters B1 and C1 are major clearance proteins at the BBB, and that these clearance mechanisms most likely are not singular event mediated by just one of these transporters. Our project aims to decipher the concerted action of the Aβ clearance. We will be able to determine whether LRP1 alone, in combination with specific ABC transporters or specific ABC transporters alone are capable to transport the majority of Aβ peptides out of the brain. Hence, we want to clarify the mechanisms behind this process and use different unique mouse models from which we will generate primary mouse brain endothelial cells to perform in vitro BBB transcytosis studies. To validate our in vitro observations, we will transfer these experimental setups into the in vivo situation by crossing the respective mouse strains and analyse BBB clearance mechanisms. Additionally, we will specifically manipulate the endothelial cells of the brain in a living mouse by using highly specific AAVs which only infect the BBB endothelium. Using this approach we will try to perform an enhanced clearance approach out of the brain. Interestingly, there are not only clearance mechanisms of waste products described out of the brain. It has also been proposed that aggregated forms of Aβ travel from peripheral tissues into the brain to seed amyloid pathology. In a recent parabiosis experiment of surgically joined AD model mice to wild-type mice it has been shown that human Aβ42 accumulates in the brains of wild-type animals. This may imply that there is a direct route of peripheral Aβ-peptides into the brain. To analyse this we will make use of our in vitro and in vivo settings and determine if and to which extend such transport routes exist.Taken together we will be able to decipher the molecular mechanism of BBB Aβ-transport using state of the art in vitro and in vivo applications. The combined efforts and expertise of the Pahnke and Pietrzik laboratories offer unique model systems which will be combined to answer the important question how and to which extent the BBB influences the clearance out of the brain and potentially the influx of Aβ-peptides into the brain.