Title |
URMC-099 facilitates amyloid-β clearance in a murine model of Alzheimer’s disease
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Published in |
Journal of Neuroinflammation, May 2018
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DOI | 10.1186/s12974-018-1172-y |
Pubmed ID | |
Authors |
Tomomi Kiyota, Jatin Machhi, Yaman Lu, Bhagyalaxmi Dyavarshetty, Maryam Nemati, Gang Zhang, R. Lee Mosley, Harris A. Gelbard, Howard E. Gendelman |
Abstract |
The mixed lineage kinase type 3 inhibitor URMC-099 facilitates amyloid-beta (Aβ) clearance and degradation in cultured murine microglia. One putative mechanism is an effect of URMC-099 on Aβ uptake and degradation. As URMC-099 promotes endolysosomal protein trafficking and reduces Aβ microglial pro-inflammatory activities, we assessed whether these responses affect Aβ pathobiogenesis. To this end, URMC-099's therapeutic potential, in Aβ precursor protein/presenilin-1 (APP/PS1) double-transgenic mice, was investigated in this model of Alzheimer's disease (AD). Four-month-old APP/PS1 mice were administered intraperitoneal URMC-099 injections at 10 mg/kg daily for 3 weeks. Brain tissues were examined by biochemical, molecular and immunohistochemical tests. URMC-099 inhibited mitogen-activated protein kinase 3/4-mediated activation and attenuated β-amyloidosis. Microglial nitric oxide synthase-2 and arginase-1 were co-localized with lysosomal-associated membrane protein 1 (Lamp1) and Aβ. Importatly, URMC-099 restored synaptic integrity and hippocampal neurogenesis in APP/PS1 mice. URMC-099 facilitates Aβ clearance in the brain of APP/PS1 mice. The multifaceted immune modulatory and neuroprotective roles of URMC-099 make it an attractive candidate for ameliorating the course of AD. This is buttressed by removal of pathologic Aβ species and restoration of the brain's microenvironment during disease. |
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Geographical breakdown
Country | Count | As % |
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Unknown | 27 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Student > Bachelor | 5 | 19% |
Student > Master | 3 | 11% |
Student > Doctoral Student | 2 | 7% |
Student > Ph. D. Student | 2 | 7% |
Professor | 1 | 4% |
Other | 2 | 7% |
Unknown | 12 | 44% |
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Agricultural and Biological Sciences | 2 | 7% |
Immunology and Microbiology | 2 | 7% |
Medicine and Dentistry | 2 | 7% |
Other | 3 | 11% |
Unknown | 12 | 44% |