Rationale: The blood-brain barrier (BBB) is a major impediment to therapeutic intracranial drug delivery for the treatment of neurodegenerative diseases, including Alzheimer's disease (AD). Focused ultrasound applied together with microbubbles (FUS +MB ) is a novel technique to transiently open the BBB and increase drug delivery. Evidence suggests that FUS +MB is safe, however, the effects of FUS +MB on human BBB cells, especially in the context of AD, remain sparsely investigated. In addition, there currently are no cell platforms to test for FUS +MB -mediated drug delivery. Methods: Here we generated BBB cells (induced brain endothelial-like cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 ( APOE4 , high sporadic AD risk) and allele E3 ( APOE3 , lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We established mono- and co-culture models of human sporadic AD and control BBB cells to investigate the effects of FUS +MB on BBB cell phenotype and to screen for the delivery of two potentially therapeutic AD antibodies, an Aducanumab-analogue (Aduhelm TM ; anti-amyloid-β) and a novel anti-Tau antibody, RNF5. We then developed a novel hydrogel-based 2.5D BBB model as a step towards a more physiologically relevant FUS +MB drug delivery platform. Results: When compared to untreated cells, the delivery of Aducanumab-analogue and RNF5 was significantly increased (up to 1.73 fold), across the Transwell-based BBB models following FUS +MB treatment. Our results also demonstrated the safety of FUS +MB indicated by minimal changes in iBEC transcriptome as well as little or no changes in iBEC or iAstrocyte viability and inflammatory responses within the first 24 h post FUS +MB . Furthermore, we demonstrated successful iBEC barrier formation in our novel 2.5D hydrogel-based BBB model with significantly increased delivery (1.4 fold) of Aducanumab-analogue following FUS +MB . Conclusion: Our results demonstrate a robust and reproducible approach to utilize patient cells for FUS +MB -mediated drug delivery screening in vitro . With such a cell platform for FUS +MB research previously not reported, it has the potential to identify novel FUS +MB -deliverable drugs as well as screen for cell- and patient-specific effects of FUS +MB , accelerating the use of FUS +MB as a therapeutic modality in AD.

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Physical exercise can attenuate the effects of aging on the central nervous system by increasing the expression of neurotrophins such as brain-derived neurotrophic factor (BDNF), which promotes dendritic branching and enhances synaptic machinery, through interaction with its receptor TrkB. TrkB receptors are synthesized in the cell body and are transported to the axonal terminals and anchored to plasma membrane, through SLP1, CRMP2 and Rab27B, associated with KIF1B. Retrograde trafficking is made by EDH-4 together with dynactin and dynein molecular motors. In the present study it was found that early neurodegeneration is accompanied by decrease in BDNF signaling, in the absence of hyperphosphorylated tau aggregation, in hippocampus of 11 months old Lewis rats exposed to rotenone. It was also demonstrated that moderate physical activity (treadmill running, during 6 weeks, concomitant to rotenone exposure) prevents the impairment of BDNF system in aged rats, which may contribute to delay neurodegeneration. In conclusion, decrease in BDNF and TrkB vesicles occurs before large aggregate-like p-Tau are formed and physical activity applied during early neurodegeneration may be of relevance to prevent BDNF system decay.

The blood-brain barrier is a semipermeable barrier structure that lines the walls of brain microvessels. Although the blood-brain barrier plays a key role in protecting the brain from unwanted molecules, it simultaneously challenges the delivery of drugs into the brain. In addition, the blood-brain barrier has been shown to be dysfunctional in Alzheimer' s disease, the most common cause of dementia for which there is no cure. Mouse models of Alzheimer' s disease have played a central role in investigating disease-specific changes in the blood-brain barrier, but the translation of findings from mouse models into the human system is hindered by interspecies differences. In an effort to develop new drug delivery techniques and/or understand changes in the human blood-brain barrier in Alzheimer' s disease, several human blood-brain barrier in vitro models have been developed. These comprise primary and immortalized human endothelial cell-based models as well as human induced pluripotent stem cell-derived brain microvascular endothelial cell models. Both two-and three-dimensional

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