Showing papers by "Clive N. Svendsen published in 2019"

Young bone marrow transplantation preserves learning and memory in old mice

Abstract: Restoration of cognitive function in old mice by transfer of blood or plasma from young mice has been attributed to reduced C–C motif chemokine ligand 11 (CCL11) and β2-microglobulin, which are thought to suppress neurogenesis in the aging brain. However, the specific role of the hematopoietic system in this rejuvenation has not been defined and the importance of neurogenesis in old mice is unclear. Here we report that transplantation of young bone marrow to rejuvenate the hematopoietic system preserved cognitive function in old recipient mice, despite irradiation-induced suppression of neurogenesis, and without reducing β2-microglobulin. Instead, young bone marrow transplantation preserved synaptic connections and reduced microglial activation in the hippocampus. Circulating CCL11 levels were lower in young bone marrow recipients, and CCL11 administration in young mice had the opposite effect, reducing synapses and increasing microglial activation. In conclusion, young blood or bone marrow may represent a future therapeutic strategy for neurodegenerative disease. Melanie Das et al. demonstrate that transplantation of young bone marrow preserves the cognitive function of old recipient mice. This study suggests that microglial rejuvenation via peripheral manipulation of the hematopoietic system may be sufficient to delay a cognitive decline during aging.

Huntington's disease patient-derived astrocytes display electrophysiological impairments and reduced neuronal support

Abstract: In Huntington’s disease (HD), while the ubiquitously expressed mutant Huntingtin (mtHTT) protein primarily compromises striatal and cortical neurons, glia also undergo disease-contributing alterations. Existing HD models using human induced pluripotent stem cells (iPSCs) have not extensively characterized the role of mtHTT in patient-derived astrocytes. Here physiologically mature astrocytes are generated from HD patient iPSCs. These human astrocytes exhibit hallmark HD phenotypes that occur in mouse models, including impaired inward rectifying K+ currents, lengthened spontaneous Ca2+ waves and reduced cell membrane capacitance. HD astrocytes in co-culture provided reduced support for the maturation of iPSC-derived neurons. In addition, neurons exposed to chronic glutamate stimulation are not protected by HD astrocytes. This iPSC-based HD model demonstrates the critical effects of mtHTT on human astrocytes, which not only broadens the understanding of disease susceptibility beyond cortical and striatal neurons but also increases potential drug targets.

Quantum Capacitance Based Amplified Graphene Phononics for Studying Neurodegenerative Diseases

Abstract: Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease (MND) characterized by a rapid loss of upper and lower motor neurons resulting in patient death from respiratory failure within 3–5 years of initial symptom onset. Although at least 30 genes of major effect have been reported, the pathobiology of ALS is not well understood. Compounding this is the lack of a reliable laboratory test which can accurately diagnose this rapidly deteriorating disease. Herein, we report on the phonon vibration energies of graphene as a sensitive measure of the composite dipole moment of the interfaced cerebrospinal fluid (CSF) that includes a signature-composition specific to the patients with ALS disease. The second-order overtone of in-plane phonon vibration energy (2D peak) of graphene shifts by 3.2 ± 0.5 cm–1 for all ALS patients studied in this work. Further, the amount of n-doping-induced shift in the phonon energy of graphene, interfaced with CSF, is specific to the investigated neuro...

In Vitro and In Vivo Proteomic Comparison of Human Neural Progenitor Cell-Induced Photoreceptor Survival.

Abstract: Retinal degenerative diseases lead to blindness with few treatments. Various cell-based therapies are aimed to slow the progression of vision loss by preserving light-sensing photoreceptor cells. A subretinal injection of human neural progenitor cells (hNPCs) into the Royal College of Surgeons (RCS) rat model of retinal degeneration has aided in photoreceptor survival, though the mechanisms are mainly unknown. Identifying the retinal proteomic changes that occur following hNPC treatment leads to better understanding of neuroprotection. To mimic the retinal environment following hNPC injection, a co-culture system of retinas and hNPCs is developed. Less cell death occurs in RCS retinal tissue co-cultured with hNPCs than in retinas cultured alone, suggesting that hNPCs provide retinal protection in vitro. Comparison of ex vivo and in vivo retinas identifies nuclear factor (erythroid-derived 2)-like 2 (NRF2) mediated oxidative response signaling as an hNPC-induced pathway. This is the first study to compare proteomic changes following treatment with hNPCs in both an ex vivo and in vivo environment, further allowing the use of ex vivo modeling for mechanisms of retinal preservation. Elucidation of the protein changes in the retina following hNPC treatment may lead to the discovery of mechanisms of photoreceptor survival and its therapeutic for clinical applications.

Novel differentiation technique to generate dopaminergic neurons from induced pluripotent stem cells

Abstract: Induced Pluripotent Stem Cell (Ipsc) technology enables the generation and study of living brain tissue relevant to Parkinson's disease (PD) ex vivo. Utilizing cell lines from PD patients presents a powerful discovery system that links cellular phenotypes observed in vitro with real clinical data. Differentiating patient-derived iPSCs towards a dopaminergic (DA) neural fate revealed that these cells exhibit molecular and functional properties of DA neurons in vitro that are observed to significantly degenerate in the substantia nigra of PD patients. Clinical symptoms that drive the generation of other relevant cell types may also yield novel PD-specific phenotypes in vitro that have the potential to lead to new therapeutic avenues for patients with PD. Due to their early onset and non-familial origin, differentiated nervous tissue from these patients offer a key opportunity to discover neuron subtype-specific pathological mechanisms and importantly interrogate the contribution of their genetic background in susceptibility to PD.

Isogenic blood-brain barrier model

Abstract: A method of creating an isogenic multicellular blood-brain barrier model from iPSCs is disclosed.