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Background The blood-brain barrier (BBB) has a major role in maintaining homeostasis of the brain. The primary function of the BBB is regulating the entry of molecules from the blood to the brain while protecting the brain from potentially harmful endogenous and exogenous substances. Transporters expressed in brain endothelial cells (BECs) mediate the uptake or efflux of compounds to and from the brain and they can also challenge the delivery of drugs into the brain for the treatment of brain disorders including Alzheimer’s disease (AD). AD is the most common form of dementia, however, currently there is limited understanding of the role of BBB transporters in AD-related BBB dysfunction. Methods We investigated differences in BBB transporter expression and activity in brain endothelial-like cells (iBECs) differentiated from induced pluripotent stem cells (iPSCs) obtained from people carrying the familial AD Presenilin 1 (PSEN1) mutation (PSEN1 exon 9 deletion; AD-iBECs), healthy controls (Ctrl-iBECs), and isogenic PSEN1 exon 9-corrected lines (PSEN1COR-iBECs). We first characterized the expression levels of 12 BBB transporters in AD-, Ctrl-, and isogenic iBECs to identify any AD specific differences. We then exposed the cells to focused ultrasound, in the absence (FUSonly) or presence of microbubbles (FUS+MB), to examine whether the expression or activity of key transporters can be modulated by therapeutic ultrasound, a novel technique allowing for transient BBB opening. Results Our results identified differences in the expression of BBB transporters between AD-iBECs and control iBECs, suggesting disease-specific effects on transporter expression. Additionally, our results demonstrated FUSonly and FUS+MB have the potential to modulate efflux transporter activity. Interestingly, AD-iBECs demonstrated significantly reduced PGP-mediated Aβ accumulation following FUS+MB, an effect not seen in Ctrl-iBECs, suggesting disease-related differences. Conclusions Our findings demonstrate that PSEN1 mutant AD-iBECs possess phenotypical differences compared to PSEN1 corrected and unrelated control iBECs in BBB transporter expression and function. Additionally, we show that FUSonly and FUS+MB can modulate the BBB transporter expression and functional activity in iBECs, having potential implications on drug penetration and amyloid clearance. These findings highlight the differential responses of patient cells to FUS treatment, with patient-derived models likely providing an important tool for modelling of therapeutic effects of FUS.

RationaleThe 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+MBis safe, however the effects of FUS+MBon human BBB cells, especially in the context of AD, remain sparsely investigated.MethodsHere we generated BBB cells (induced brain endothelial cells (iBECs) and astrocytes (iAstrocytes)) from apolipoprotein E gene allele E4 (APOE4, high AD risk) and allele E3 (APOE3, lower AD risk) carrying patient-derived induced pluripotent stem cells (iPSCs). We then developed a human sporadic AD BBB cell platform to investigate the effects of FUS+MBon BBB cells and screen for the delivery of two potentially therapeutic AD antibodies.ResultsWe utilized this robust and reproducible human BBB model to demonstrate increased delivery of therapeutic AD antibodies across the BBB following FUS+MBtreatment, including an analogue of Aducanumab (AduhelmTM; anti-amyloid-β) and a novel anti-Tau antibody RNF5. Our results also demonstrate the safety of FUS+MBindicated by minimal changes in the cell transcriptome as well as little or no changes in cell viability and inflammatory responses within the first 24 h post FUS+MB. Finally, we report a more physiologically relevant hydrogel-based 2.5D BBB model as a key development for FUS+MB-mediated drug delivery screening, with potentially higher translational utility.ConclusionOur results demonstrate an important translatable patient BBB cell model for identifying FUS+MB-deliverable drugs and screening for cell- and patient-specific effects of FUS+MB, accelerating the use of FUS+MBas a therapeutic modality in AD.One Sentence SummaryFocused ultrasound increases thein vitrodelivery of therapeutic antibodies Aducanumab and anti-Tau in a sporadic Alzheimer’s disease patient-derived blood-brain barrier cell model.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with extremely limited therapeutic options. Abnormal accumulation of misfolded and aggregated proteins in the soma of motor neurons is one of the main pathological hallmarks of ALS. Hence, reducing the burden of misfolded protein in motor neurons has emerged as a promising therapeutic approach to control the disease. Antisense oligonucleotides (ASOs) carry the potential to effectively silence proteins with gain-of-function mutations, such as superoxide dismutase 1 (SOD1). However, the extremely poor blood-brain barrier (BBB) penetration of ASOs and invasiveness of current intrathecal delivery methods, warrant the development of alternative strategies for the delivery of ASOs to the central nervous system (CNS). In the current study, we report the effective delivery of a next-generation SOD1 ASO (Tofersen) into the brain of mice using calcium phosphate lipid nanoparticles following systemic delivery. Most importantly, for the first time, we demonstrate the superior capability of transcranial focused ultrasound (FUS) with intravenously administered microbubbles to significantly improve the delivery of ASO-loaded nanoparticles into the mouse brain compared to control mice receiving FUS without microbubbles. Histological examination in combination with contrast enhanced MRI suggests that the opening of the BBB in this context is transient and without evidence of any perturbation in the neural micro environment, parenchymal injury or necrosis indicating the treatment is well tolerated. Further in vivo evaluation of this strategy could lead to the development of a promising new approach for therapeutic delivery to treat ALS in patients.

Functional plasticity of the brain decreases during ageing causing marked deficits in contextual learning, allocentric navigation and episodic memory. Adult neurogenesis is a prime example of hippocampal plasticity promoting the contextualisation of information and dramatically decreases during ageing. We found that a genetically-driven expansion of neural stem cells by overexpression of the cell cycle regulators Cdk4/cyclinD1 compensated the age-related decline in neurogenesis. This triggered an overall inhibitory effect on the trisynaptic hippocampal circuit resulting in a changed profile of CA1 sharp-wave ripples known to underlie memory consolidation. Most importantly, increased neurogenesis rescued the age-related switch from hippocampal to striatal learning strategies by rescuing allocentric navigation and contextual memory. Our study demonstrates that critical aspects of hippocampal function can be reversed in old age, or compensated throughout life, by exploiting the brain’s endogenous reserve of neural stem cells., Ageing affects several brain areas causing a decrease in cognitive abilities and memory. We find that increasing the endogenous potential of the hippocampus to generate new neurons throughout life rejuvenates learning and memory, indicating that neural reserves can be exploited during ageing to compensate for age- or disease-related cognitive impairments.

Background: Rodent and human studies indicate that testosterone has an antidepressant effect. The mechanisms via which testosterone exerts its antidepressant effect, however, remain to be elucidated. Some studies assume downstream effects of testosterone on sexual function and vitality followed by improvement of mood. Emerging evidence suggests that testosterone may be acting in the brain within depression-relevant areas, whereby eliciting direct antidepressant effects, potentially via neuroplasticity. Methods: Literature was searched focusing on testosterone treatment and depression and depression-like behavior. Due to the unilateral clinical use of testosterone in men and the different modes of action of sex hormones in the central nervous system in men and women, predominantly studies on male populations were identified. Results: The two proposed mechanisms via which testosterone might act as antidepressant in the central nervous system are the support of neuroplasticity as well as the activation of the serotonin system. Additionally, testosterone downregulates glucocorticoid output and reduces levels of pro-inflammatory markers, thereby acting as important counter regulatory agent reducing levels of neurotoxic factors in the central nervous system. Conclusion: Although it is possible that testosterone acts via the serotonin system or the downregulation of the immune or hyperactive stress physiological systems, recent evidence supports the hypothesis that testosterone also elicits anti-depressant effects via directly promoting neuroplasticity. Potential implementations of testosterone treatment in mood disorders are discussed.

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 (2D and 3D) culture platforms have been established to better mimic the complexity of the brain. This chapter discusses the current blood–brain barrier models, their advantages and disadvantages as well as their potential to understand drug delivery in Alzheimer’s disease.

There is growing evidence that both peripheral and resident immune cells play an important part in regulating adult neural stem cell proliferation and neurogenesis, although the contribution of the various immune cell types is still unclear. Mast cells, a population of immune cells known for their role in the allergic response, have been implicated in the regulation of adult hippocampal neurogenesis. Mast cell-deficient c-kit

Although the neurogenesis-enhancing effects of exercise have been extensively studied, the molecular mechanisms underlying this response remain unclear. Here, we propose that this is mediated by the exercise-induced systemic release of the antioxidant selenium transport protein, selenoprotein P (SEPP1). Using knockout mouse models, we confirmed that SEPP1 and its receptor low-density lipoprotein receptor-related protein 8 (LRP8) are required for the exercise-induced increase in adult hippocampal neurogenesis. In vivo selenium infusion increased hippocampal neural precursor cell (NPC) proliferation and adult neurogenesis. Mimicking the effect of exercise through dietary selenium supplementation restored neurogenesis and reversed the cognitive decline associated with aging and hippocampal injury, suggesting potential therapeutic relevance. These results provide a molecular mechanism linking exercise-induced changes in the systemic environment to the activation of quiescent hippocampal NPCs and their subsequent recruitment into the neurogenic trajectory.

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There is growing evidence that both peripheral and resident immune cells play an important part in regulating adult neural stem cell proliferation and neurogenesis, although the contribution of the various immune cell types is still unclear. Mast cells, a population of immune cells known for their role in the allergic response, have been implicated in the regulation of adult hippocampal neurogenesis. Mast cell-deficient c-kitW-sh/W-sh mice have previously been shown to exhibit significantly decreased adult hippocampal neurogenesis and associated learning and memory deficits. However, given that numerous other cell types also express high levels of c-kit, the utility of these mice as a reliable model of mast cell-specific depletion is questionable. We show here, using a different model of mast cell deficiency (Mcpt5CreR26DTA/DTA), that precursor proliferation and adult neurogenesis are not influenced by mast cells in vivo. Interestingly, when applied at supraphysiological doses, mast cells can activate latent hippocampal precursor cells and increase subventricular zone precursor proliferation in vitro, an effect that can be blocked with specific histamine-receptor antagonists. Thus, we conclude that while both mast cells and their major chemical mediator histamine have the potential to affect neural precursor proliferation and neurogenesis, this is unlikely to occur under physiological conditions., Scientific Reports, 7, ISSN:2045-2322