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J Neuroinflammation. 2018 May 5;15(1):137. doi: 10.1186/s12974-018-1172-y.

URMC-099 facilitates amyloid-β clearance in a murine model of Alzheimer's disease.

Author information

1
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA.
2
Department of Safety Assessment, Genentech Inc., South San Francisco, CA, USA.
3
Department of Pediatrics, University of California San Diego, La Jolla, CA, USA.
4
Center for Neurotherapeutics Discovery, School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, NY, USA.
5
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, USA. hegendel@unmc.edu.
6
Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE, USA. hegendel@unmc.edu.
7
Department of Pharmacology and Experimental Neuroscience, 985880 Nebraska Medical Center, Omaha, NE, 68198-5880, USA. hegendel@unmc.edu.

Abstract

BACKGROUND:

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).

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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.

PMID:
29729668
PMCID:
PMC5935963
DOI:
10.1186/s12974-018-1172-y
[Indexed for MEDLINE]
Free PMC Article

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