Browsing by Subject "neurodegenerative diseases"

Now showing 1 - 3 of 3
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    The Alzheimer's Disease Sequencing Project: Study design and sample selection
    (Lippincott, Williams & Wilkins, 2017-10-13) Beecham, Gary W.; Bis, J.C.; Martin, E.R.; Choi, S.-H.; DeStefano, A. L.; van Duijn, C.M.; Fornage, M.; Gabriel, S.B.; Koboldt, D.C.; Larson, D.E.; Naj, A.C.; Psaty, B.M.; Salerno, W.; Bush, W.S.; Foroud, T.M.; Wijsman, E.; Farrer, L.A.; Goate, A.; Haines, J.L.; Pericak-Vance, Margaret A.; Boerwinkle, E.; Mayeux, R.; Seshadri, S.; Schellenberg, G.; Medical and Molecular Genetics, School of Medicine
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    The Ex Vivo Human Translaminar Autonomous System to Study Spaceflight Associated Neuro-ocular Syndrome Pathogenesis
    (Nature, 2022-10) Peng, Michael; Curry, Stacy M.; Liu, Yang; Lohawala, Husain; Sharma, Gaurav; Sharma, Tasneem P.; Ophthalmology, School of Medicine
    Spaceflight-Associated Neuro-ocular Syndrome (SANS) is a significant unexplained adverse reaction to long-duration spaceflight. We employ an ex vivo translaminar autonomous system (TAS) to recreate a human ocular ground-based spaceflight analogue model to study SANS pathogenesis. To recapitulate the human SANS conditions, human ocular posterior segments are cultured in the TAS model for 14 days. Translaminar pressure differentials are generated by simulating various flow rates within intracranial pressure (ICP) and intraocular (IOP) chambers to maintain hydrostatic pressures of ICP: IOP (12:16, 15:16, 12:21, 21:16 mmHg). In addition, optic nerves are mechanically kinked by 6- and 10-degree tilt inserts for the ICP: IOP;15:16 mmHg pressure paradigm. The TAS model successfully maintains various pressure differentials for all experimental groups over 14 days. Post culture, we determine inflammatory and extracellular component expression changes within posterior segments. To further characterize the SANS pathogenesis, axonal transport capacity, optic nerve degeneration and retinal functional are measured. Identifiable pathogenic alterations are observed in posterior segments by morphologic, apoptotic, and inflammatory changes including transport and functional deficits under various simulated SANS conditions. Here we report our TAS model provides a unique preclinical application system to mimic SANS pathology and a viable therapeutic testing device for countermeasures.
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    PPARβ/δ-agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes
    (Wiley, 2018-11-19) Konttinen, Henna; Gureviciene, Irina; Oksanen, Minna; Grubman, Alexandra; Loppi, Sanna; Huuskonen, Mikko T.; Korhonen, Paula; Lampinen, Riikka; Keuters, Meike; Belaya, Irina; Tanila, Heikki; Kanninen, Katja M.; Goldsteins, Gundars; Landreth, Gary; Koistinaho, Jari; Malm, Tarja; Anatomy and Cell Biology, School of Medicine
    Astrocytes are the gatekeepers of neuronal energy supply. In neurodegenerative diseases, bio-energetics demand increases and becomes reliant upon fatty acid oxidation as a source of energy. Defective fatty acid oxidation and mitochondrial dysfunctions correlate with hippocampal neurodegeneration and memory deficits in Alzheimer’s disease (AD), but it is unclear whether energy metabolism can be targeted to prevent or treat the disease. Here we show for the first time an impairment in fatty acid oxidation in human astrocytes derived from induced pluripotent stem cells of AD patients. The impairment was corrected by treatment with a synthetic peroxisome proliferator activated receptor delta (PPARβ/δ) agonist GW0742 which acts to regulate an array of genes governing cellular metabolism. GW0742 enhanced the expression of CPT1a, the gene encoding for a rate-limiting enzyme of fatty acid oxidation. Similarly, treatment of a mouse model of AD, the APP/PS1-mice, with GW0742 increased the expression of Cpt1a and concomitantly reversed memory deficits in a fear conditioning test. Although the GW0742-treated mice did not show altered astrocytic glial fibrillary acidic protein-immunoreactivity or reduction in amyloid beta (Aβ) load, GW0742 treatment increased hippo-campal neurogenesis and enhanced neuronal differentiation of neuronal progenitor cells. Furthermore, GW0742 prevented Aβ-induced impairment of long-term potentiation in hippocampal slices. Collectively, these data suggest that PPARβ/δ-agonism alleviates AD related deficits through increasing fatty acid oxidation in astrocytes and improves cognition in a transgenic mouse model of AD.