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1. Beta-Amyloid Instigates Dysfunction of Mitochondria in Cardiac Cells

   https://doi.org/10.3390/cells11030373  

   Jang, Sehwan; Chapa-Dubocq, Xavier R.; Parodi-Rullán, Rebecca M.; Fossati, Silvia; Javadov, Sabzali (February 2022, Cells)

   Alzheimer’s disease (AD) includes the formation of extracellular deposits comprising aggregated β-amyloid (Aβ) fibers associated with oxidative stress, inflammation, mitochondrial abnormalities, and neuronal loss. There is an associative link between AD and cardiac diseases; however, the mechanisms underlying the potential role of AD, particularly Aβ in cardiac cells, remain unknown. Here, we investigated the role of mitochondria in mediating the effects of Aβ1-40 and Aβ1-42 in cultured cardiomyocytes and primary coronary endothelial cells. Our results demonstrated that Aβ1-40 and Aβ1-42 are differently accumulated in cardiomyocytes and coronary endothelial cells. Aβ1-42 had more adverse effects than Aβ1-40 on cell viability and mitochondrial function in both types of cells. Mitochondrial and cellular ROS were significantly increased, whereas mitochondrial membrane potential and calcium retention capacity decreased in both types of cells in response to Aβ1-42. Mitochondrial dysfunction induced by Aβ was associated with apoptosis of the cells. The effects of Aβ1-42 on mitochondria and cell death were more evident in coronary endothelial cells. In addition, Aβ1-40 and Aβ1-42 significantly increased Ca2+ -induced swelling in mitochondria isolated from the intact rat hearts. In conclusion, this study demonstrates the toxic effects of Aβ on cell survival and mitochondria function in cardiac cells. 

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2. TERMIS AM

   Yeoheung Yun, Balqees Khader (April 2023, Three-dimensional Alzheimer's disease's spheroid grafted neurovascular unit)

   Alzheimer’s disease (AD) is characterized by distinct tissue changes associated with accumulation of extracellular amyloid-beta (Aβ) peptides, and intracellular deposits of phosphorylated Tau (p-tau). There is a clear need to develop 3D AD model for alternative to animal test since current rodent model does not recapitulate complex human AD physiopathology. Here we report on organoid-grafted neurovascular unit (NUV) using 1) spheroid using APP-mutated neuro-progenitor cell and 2) endothelial-based blood brain barrier (BBB) against extracellular matrix. The construct was validated with AD pathology generation and further treatment with β- or γ-secretase inhibitors shows the decrease of Aβ. This paper demonstrates the potential utility of a membrane-free in vitro cortical spheroid tissue construct with BBB in a high throughput platform to model AD. 

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3. Optimization and Technical Considerations for the Dye-Exclusion Protocol Used to Assess Blood–Brain Barrier Integrity in Adult Drosophila melanogaster

   https://doi.org/10.3390/ijms24031886  

   Bhasiin, Kesshni; Heintz, Olivia; Colodner, Kenneth J. (February 2023, International Journal of Molecular Sciences)

   The blood–brain barrier (BBB) is a multicellular construct that regulates the diffusion and transport of metabolites, ions, toxins, and inflammatory mediators into and out of the central nervous system (CNS). Its integrity is essential for proper brain physiology, and its breakdown has been shown to contribute to neurological dysfunction. The BBB in vertebrates exists primarily through the coordination between endothelial cells, pericytes, and astrocytes, while invertebrates, which lack a vascularized circulatory system, typically have a barrier composed of glial cells that separate the CNS from humoral fluids. Notably, the invertebrate barrier is molecularly and functionally analogous to the vertebrate BBB, and the fruit fly, Drosophila melanogaster, is increasingly recognized as a useful model system in which to investigate barrier function. The most widely used technique to assess barrier function in the fly is the dye-exclusion assay, which involves monitoring the infiltration of a fluorescent-coupled dextran into the brain. In this study, we explore analytical and technical considerations of this procedure that yield a more reliable assessment of barrier function, and we validate our findings using a traumatic injury model. Together, we have identified parameters that optimize the dye-exclusion assay and provide an alternative framework for future studies examining barrier function in Drosophila. 

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4. N -Amino peptide scanning reveals inhibitors of Aβ ₄₂ aggregation

   https://doi.org/10.1039/D0RA02009E  

   Tillett, Khalilia C.; Del Valle, Juan R. (April 2020, RSC Advances)

   The aggregation of amyloids into toxic oligomers is believed to be a key pathogenic event in the onset of Alzheimer's disease. Peptidomimetic modulators capable of destabilizing the propagation of an extended network of β-sheet fibrils represent a potential intervention strategy. Modifications to amyloid-beta (Aβ) peptides derived from the core domain have afforded inhibitors capable of both antagonizing aggregation and reducing amyloid toxicity. Previous work from our laboratory has shown that peptide backbone amination stabilizes β-sheet-like conformations and precludes β-strand aggregation. Here, we report the synthesis of N -aminated hexapeptides capable of inhibiting the fibrillization of full-length Aβ 42 . A key feature of our design is N -amino substituents at alternating backbone amides within the aggregation-prone Aβ 16–21 sequence. This strategy allows for maintenance of an intact hydrogen-bonding backbone edge as well as side chain moieties important for favorable hydrophobic interactions. An N -amino scan of Aβ 16–21 resulted in the identification of peptidomimetics that block Aβ 42 fibrilization in several biophysical assays. 

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5. Potential crosstalk between sonic hedgehog‐WNT signaling and neurovascular molecules: Implications for blood–brain barrier integrity in autism spectrum disorder

   https://doi.org/10.1111/jnc.15460  

   Gozal, Evelyne; Jagadapillai, Rekha; Cai, Jun; Barnes, Gregory N. (June 2021, Journal of Neurochemistry)

   null (Ed.)

   Autism Spectrum Disorder (ASD) is a neurodevelopmental disease originating from combined genetic and environmental factors. Post-mortem human studies and some animal ASD models have shown brain neuroinflammation, oxidative stress, and changes in blood–brain barrier (BBB) integrity. However, the signaling pathways leading to these inflammatory findings and vascular alterations are currently unclear. The BBB plays a critical role in controlling brain homeostasis and immune response. Its dysfunction can result from developmental genetic abnormalities or neuroinflammatory processes. In this review, we explore the role of the Sonic Hedgehog/Wingless-related integration site (Shh/Wnt) pathways in neurodevelopment, neuroinflammation, and BBB development. The balance between Wnt-β-catenin and Shh pathways controls angiogenesis, barriergenesis, neurodevelopment, central nervous system (CNS) morphogenesis, and neuronal guidance. These interactions are critical to maintain BBB function in the mature CNS to prevent the influx of pathogens and inflammatory cells. Genetic mutations of key components of these pathways have been identified in ASD patients and animal models, which correlate with the severity of ASD symptoms. Disruption of the Shh/Wnt crosstalk may therefore compromise BBB development and function. In turn, impaired Shh signaling and glial activation may cause neuroinflammation that could disrupt the BBB. Elucidating how ASD-related mutations of Shh/Wnt signaling could cause BBB leaks and neuroinflammation will contribute to our understanding of the role of their interactions in ASD pathophysiology. These observations may provide novel targeted therapeutic strategies to prevent or alleviate ASD symptoms while preserving normal developmental processes. 

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