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

Tomomi Kiyota, Jatin Machhi, Yaman Lu, Bhagyalaxmi Dyavarshetty, Maryam Nemati, Gang Zhang, R Lee Mosley, Harris A. Gelbard, Howard Eliot Gendelman

Research output: Contribution to journalArticle

5 Citations (Scopus)

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.

Original languageEnglish (US)
Article number137
JournalJournal of Neuroinflammation
Volume15
Issue number1
DOIs
StatePublished - May 5 2018

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Amyloid
Alzheimer Disease
Protein Precursors
Lysosomal-Associated Membrane Protein 1
Brain
Presenilin-1
URMC-099
Arginase
Mitogen-Activated Protein Kinase 3
Neurogenesis
Microglia
Amyloidosis
Protein Transport
Nitric Oxide Synthase
Transgenic Mice
Injections

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology
  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

URMC-099 facilitates amyloid-β clearance in a murine model of Alzheimer's disease. / Kiyota, Tomomi; Machhi, Jatin; Lu, Yaman; Dyavarshetty, Bhagyalaxmi; Nemati, Maryam; Zhang, Gang; Mosley, R Lee; Gelbard, Harris A.; Gendelman, Howard Eliot.

In: Journal of Neuroinflammation, Vol. 15, No. 1, 137, 05.05.2018.

Research output: Contribution to journalArticle

Kiyota, Tomomi ; Machhi, Jatin ; Lu, Yaman ; Dyavarshetty, Bhagyalaxmi ; Nemati, Maryam ; Zhang, Gang ; Mosley, R Lee ; Gelbard, Harris A. ; Gendelman, Howard Eliot. / URMC-099 facilitates amyloid-β clearance in a murine model of Alzheimer's disease. In: Journal of Neuroinflammation. 2018 ; Vol. 15, No. 1.
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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.",
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