The blood–brain barrier (BBB) regulates the delivery of oxygen and important nutrients to the brain through active and passive transport and prevents neurotoxins from entering the brain. It also has a clearance function and removes carbon dioxide and toxic metabolites from the central nervous system (CNS). Several drugs are unable to cross the BBB and enter the CNS, adding complexity to drug screens targeting brain disorders. A well-functioning BBB is essential for maintaining healthy brain tissue, and a malfunction of the BBB, linked to its permeability, results in toxins and immune cells entering the CNS. This impairment is associated with a variety of neurological diseases, including Alzheimer’s disease and Parkinson’s disease. Here, we summarize current knowledge about the BBB in neurodegenerative diseases. Furthermore, we focus on recent progress of using human-induced pluripotent stem cell (iPSC)-derived models to study the BBB. We review the potential of novel stem cell-based platforms in modeling the BBB and address advances and key challenges of using stem cell technology in modeling the human BBB. Finally, we highlight future directions in this area.

During development, neurons achieve a stereotyped neuron type-specific morphology, which relies on dynamic support by microtubules (MTs). An important player is the augmin complex (hereafter augmin), which binds to existing MT filaments and recruits the γ-tubulin ring complex (γ-TuRC), to form branched MTs. In cultured neurons, augmin is important for neurite formation. However, little is known about the role of augmin during neurite formation in vivo. Here, we have revisited the role of mammalian augmin in culture and then turned towards the class four Drosophila dendritic arborization (c4da) neurons. We show that MT density is maintained through augmin in cooperation with the γ-TuRC in vivo. Mutant c4da neurons show a reduction of newly emerging higher-order dendritic branches and in turn also a reduced number of their characteristic space-filling higher-order branchlets. Taken together, our data reveal a cooperative function for augmin with the γ-TuRC in forming enough MTs needed for the appropriate differentiation of morphologically complex dendrites in vivo.

Alzheimer’s disease (AD) patients often exhibit cerebral amyloid angiopathy (CAA), i.e beta-amyloid (Aβ) accumulation within cerebral blood vessels causing cerebrovascular dysfunction. Pericytes wrap around vascular capillaries, thus regulating cerebral blood flow, angiogenesis, and vessel stability. Vascular dysfunction can promote the development and progression of neurodegenerative diseases, yet the specific contribution of pericytes to AD pathology remains unclear. Here we show that human induced pluripotent stem cell (iPSC)-derived pericyte-like cells (iPLCs) can generate Aβ peptides, and that the cells carrying Swedish mutation in amyloid precursor protein (APPswe) secrete 10 times more Aβ1-42 than the control cells. Additionally, APPswe iPLCs have an impaired capacity to support angiogenesis and barrier integrity, exhibit a prolonged contractile response, and produce increased levels of pro-inflammatory cytokines upon inflammatory stimulation. These functional alterations in APPswe iPLCs are accompanied by transcriptional upregulation of actin cytoskeleton and extracellular matrix organization-related genes. Therefore, the APPswe mutation in iPLCs recapitulates several features of CAA pathology in vitro . Our iPSC-based vascular cell model may thus serve as a platform for drug discovery targeting vascular dysfunction in AD.