Boston Children's Hospital’s Post

A molecular brain map to understand Alzheimer's disease In the study, published in Nature, the authors analyzed transcriptomes of cells across six distinct brain regions that are often affected by Alzheimer's pathology. The resulting atlas, which is now available online to researchers worldwide, could be used as a tool for gene and molecular discovery across pathways affecting brain health. The authors identify 76 cell types, including region-specific subtypes of astrocytes and excitatory neurons and an inhibitory interneuron population unique to the thalamus and distinct from canonical inhibitory subclasses. They also identify vulnerable populations of excitatory and inhibitory neurons that are depleted in specific brain regions in Alzheimer’s disease, and provide evidence that the Reelin signalling pathway is involved in modulating the vulnerability of these neurons. The authors also discover gene modules that are cell-type-specific and region-specific modules which are altered in Alzheimer’s disease and to annotate transcriptomic differences associated with diverse pathological variables. The researchers also identified an astrocyte program that is associated with cognitive resilience to Alzheimer’s disease pathology, tying choline metabolism and polyamine biosynthesis in astrocytes to preserved cognitive function late in life. #ScienceMission #sciencenewshighlights https://lnkd.in/g8WWtFQt

Human brains are a complex network of cells with intricate interactions. New research from scientists at the University of California, San Diego, sheds light on how genetic components impact cellular function as brain cells age. The study reveals that certain brain cells age more rapidly in individuals with Alzheimer’s disease and demonstrates sex-specific differences in cell aging processes. The findings, detailed in a Nature paper titled, “Single-cell multiplex chromatin and RNA interactions in aging human brain,” highlight the importance of understanding these nuances for potential therapeutic interventions. Find the Nature paper linked below! #alzheimers #singlecell #RNA

Pyruvate dehydrogenase acts as "off switch" in brain cells The authors wanted to study how brain cells changed when they were actively firing—emitting an electrical charge to pass messages to their neighbors—compared to when they were done firing. The scientists used optogenetics, in which cells’ activity can be controlled using light, to repeatedly activate and inhibit the cells. Then, they measured levels and characteristics of different proteins and their modifications. They identified that one protein, pyruvate dehydrogenase (PDH), was very rapidly changed immediately after brain cells were inhibited. “When neurons are firing, you need a lot of energy, and this PDH protein is involved in producing that energy,” explains the senior auhtor. “But the brain really wants to conserve energy, so when a cell is done firing, we found that the brain rapidly shuts off the PDH protein. This happened much faster than anything else we saw in gene expression.” To shut off PDH, the researchers found, cells add molecular tags called phosphates to the protein. The authors found antibodies that only recognized this inactive, phosphorylated form of PDH (pPDH). To test whether levels of phosphorylated PDH (or pPDH) could be used as a proxy for brain cell inhibition, the team used these antibodies to measure pPDH in mice that had been given anesthesia. Nearly the entire brain lit up with high levels of pPDH, correctly showing how most of the brain is inactive during anesthesia. #ScienceMission #sciencenewshighlights https://lnkd.in/grjjP8M6

The researchers identified a specific set of neurons (ppp1r7) in the brain’s hypothalamus that, when active, sends signals to the body’s fat tissue to release energy. Using genetic and molecular methods, the researchers studied mice that were programmed to have this communication pathway constantly open after they reached a certain age. As as consequence, these mice were more physically active, showed signs of delayed aging, and lived longer than mice in which this same communication pathway gradually slowed down as part of normal aging. To be specific, ppp1r7 in hypothalamus present in the brain which govern the body's fight or flight system. As a part of this response, the neurons in the hypothalamus set off a chain of events that triggers neurons that govern white adipose tissue — a type of fat tissue — stored under the skin and in the abdominal area. As a result, fatty acids are released into the bloodstream that can be used to fuel physical activity. Together with this activation process, Another important protein are produced— an enzyme called eNAMPT — which returns to the hypothalamus and allows the brain to produce fuel for its functions. This feedback loop is critical for fueling the body and the brain, but it slows down over time. With age, the researchers found that the protein Ppp1r17 tends to leave the nucleus of the neurons, and when that happens, the neurons in the hypothalamus send weaker signals. For detailed information, please read here: https://lnkd.in/gq3ygC-9

NEW PROTOCOL ALERT. In vitro co-cultures of iPSC-derived microglia and neurons help recapitulate the complexity of the human neuroimmune system, enabling the construction of assays with improved physiological relevance, and supporting the development of more effective therapeutics for neurological disease. However, when speaking to scientists, we keep hearing how challenging the generation of functional co-cultures involving human microglia can be in terms of long, complex protocols that require considerable iPSC expertise and single donor restrictions. By following our protocol, researchers can easily generate functional neuronal co-cultures in a matter of days and can do so with both male or female donor-derived microglia to account for donor and sex-related genetic differences in their experiments. If you are looking to set up co-cultures to model the human brain, be sure to check out our 4-step protocol. Read the protocol: https://hubs.ly/Q02qyZ810 #research #DrugDiscovery #iPSC #microglia #ioMicroglia #protocol #neurodegeneration #AlzheimersDisease #cell #optiox #ioCells

Alzheimer's disease: Accumulation of Glu-5'tsRNA-CTC [a small RNA derived from transfer RNA (tsRNA), derived from tRNAGlu] in glutaminergic neuronal mitochondria alters mitochondrial protein synthesis and cristae structure, accelerating cognitive impairment. Mitochondrial Glu-5'tsRNA-CTC disrupts the binding of mt-tRNALeu and leucyl-tRNA synthetase 2 (LARS2), impairing mt-tRNALeu aminoacylation and translation of mitochondrial-encoded proteins. Defects in mitochondrial translation alter cristae architecture, resulting in impaired glutaminase-dependent glutamine (GLS) formation and reduced synaptic glutamate levels. The researchers designed antisense oligonucleotides targeting these tRNA fragments and injected them into the brains of aged mice. This intervention significantly alleviated learning and memory deficits in aged mice. Reference: Aging-induced tRNAGlu-derived fragment impairs glutamate biosynthesis by targeting mitochondrial translation-dependent cristae organization https://lnkd.in/eb8P9c6K

Protein folding factors play a key role in neurodegeneration For the first time, researchers have mapped out the proteins implicated in the early stages of motor neurone disease (MND). They have developed a longitudinal map of the proteins involved in MND across the trajectory of the disease, identifying potential therapeutic pathways for further investigation.. “Before the onset of MND in mouse models, we observed a marked increase in protein groups responsible for physically assisting in the protein folding process. “One of these ‘chaperone’ proteins, DNAJB5, was particularly abundant early on, sparking our curiosity about its role in disease progression. “In human brain tissue, we found DNAJB5 enriched in areas where TDP-43 aggregates. “The short-term elevation of DNAJB5 is likely a protective mechanism by neurons in an attempt to control TDP-43 as it begins to dysfunction. DNAJB5 over-expression decreased TDP-43 aggregation in cell and cortical neuron cultures, and knockout of Dnajb5 exacerbated motor impairments caused by AAV-mediated cytoplasmic TDP-43 expression in mice. #ScienceMission #sciencenewshighlights https://lnkd.in/giey7WFm

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Exciting advancements in understanding Parkinson's Disease at a cellular level! A recent study utilized single nucleus transcriptome analysis, revealing intriguing insights. Notably, our Molecular Cartography technology allowed a deep dive into the spatial dimension. Using a panel of cell type-specific markers, they confirmed cell proportions and validated findings from snRNA-seq. Spatial transcriptomics with single-cell resolution showcased the depletion of tyrosine hydroxylase (TH) in glial cells compared to neurons, offering valuable insights into dopaminergic neuron degeneration. Read the whole study here: https://lnkd.in/etES7vsT #parkinsonsresearch #molecularcartography #cellularanalysis #innovation