Laquinimod has no effects on brain volume or cellular CNS composition in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease

Rehana Z. Hussain, William A. Miller-Little, Doris Lambracht-Washington, Tom C. Jaramillo, Masaya Takahashi, Shanrong Zhang, Min Fu, Gary R. Cutter, Liat Hayardeny, Craig M. Powell, Roger N. Rosenberg, Olaf Stüve

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Background Laquinimod is an anti-inflammatory agent with good central nervous system (CNS) bioavailability, and neuroprotective and myelorestorative properties. A clinical trial in patients with multiple sclerosis demonstrated that laquinimod significantly reduced loss of brain volume. The cellular substrate or molecular events underlying that treatment effect are unknown. In this study, we aimed to explore laquinimod's potential effects on brain volume, animal behavior, cellular numbers and composition of CNS-intrinsic cells and mononuclear cells within the CNS, amyloid beta (Aβ) accumulation and tau phosphorylation in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Methods Utilizing a dose response study design, four months old F1 3xTg-AD/C3H mice were treated for 10 months between ages 4 and 14 months with laquinimod (5, 10, or 25 mg/kg), or PBS administered by oral gavage. Brain volumes were measured in a 7 Tesla magnetic resonance imager (MRI) at ages 4 and 14 months. Behavioral testing included locomotor and rearing activity and the Morris water maze task. Cell numbers and immunophenotypes were assessed by multiparameter flow cytometry. Aβ deposition and tau phosphorylation were determined by immunohistochemistry. Results In the F1 3xTg-AD/C3H animal model of AD, there was no detectable reduction of brain volume over a period of 10 months of treatment, as there was not brain atrophy in any of the placebo or treatment groups. Laquinimod had no detectable effects on most neurobehavioral outcomes. The number or composition of CNS intrinsic cells and mononuclear subsets isolated from the CNS were not altered by laquinimod. Conclusion This is the first demonstration that there are no age-associated brain volume changes in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Consequently, laquinimod had no effect on that outcome of this study. Most secondary outcomes on the effects of laquinimod on behavior and the number and composition of CNS-intrinsic cells and mononuclear cells within the CNS were also negative.

Original languageEnglish (US)
Pages (from-to)100-110
Number of pages11
JournalJournal of Neuroimmunology
Volume309
DOIs
StatePublished - Aug 15 2017

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Inbred C3H Mouse
Alzheimer Disease
Central Nervous System
Brain
Phosphorylation
Animal Behavior
laquinimod
Locomotion
Amyloid
Biological Availability
Multiple Sclerosis
Atrophy
Flow Cytometry
Anti-Inflammatory Agents
Magnetic Resonance Spectroscopy
Therapeutics
Animal Models
Cell Count
Immunohistochemistry
Placebos

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Neurology
  • Clinical Neurology

Cite this

Laquinimod has no effects on brain volume or cellular CNS composition in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. / Hussain, Rehana Z.; Miller-Little, William A.; Lambracht-Washington, Doris; Jaramillo, Tom C.; Takahashi, Masaya; Zhang, Shanrong; Fu, Min; Cutter, Gary R.; Hayardeny, Liat; Powell, Craig M.; Rosenberg, Roger N.; Stüve, Olaf.

In: Journal of Neuroimmunology, Vol. 309, 15.08.2017, p. 100-110.

Research output: Contribution to journalArticle

Hussain, Rehana Z. ; Miller-Little, William A. ; Lambracht-Washington, Doris ; Jaramillo, Tom C. ; Takahashi, Masaya ; Zhang, Shanrong ; Fu, Min ; Cutter, Gary R. ; Hayardeny, Liat ; Powell, Craig M. ; Rosenberg, Roger N. ; Stüve, Olaf. / Laquinimod has no effects on brain volume or cellular CNS composition in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. In: Journal of Neuroimmunology. 2017 ; Vol. 309. pp. 100-110.
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abstract = "Background Laquinimod is an anti-inflammatory agent with good central nervous system (CNS) bioavailability, and neuroprotective and myelorestorative properties. A clinical trial in patients with multiple sclerosis demonstrated that laquinimod significantly reduced loss of brain volume. The cellular substrate or molecular events underlying that treatment effect are unknown. In this study, we aimed to explore laquinimod's potential effects on brain volume, animal behavior, cellular numbers and composition of CNS-intrinsic cells and mononuclear cells within the CNS, amyloid beta (Aβ) accumulation and tau phosphorylation in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Methods Utilizing a dose response study design, four months old F1 3xTg-AD/C3H mice were treated for 10 months between ages 4 and 14 months with laquinimod (5, 10, or 25 mg/kg), or PBS administered by oral gavage. Brain volumes were measured in a 7 Tesla magnetic resonance imager (MRI) at ages 4 and 14 months. Behavioral testing included locomotor and rearing activity and the Morris water maze task. Cell numbers and immunophenotypes were assessed by multiparameter flow cytometry. Aβ deposition and tau phosphorylation were determined by immunohistochemistry. Results In the F1 3xTg-AD/C3H animal model of AD, there was no detectable reduction of brain volume over a period of 10 months of treatment, as there was not brain atrophy in any of the placebo or treatment groups. Laquinimod had no detectable effects on most neurobehavioral outcomes. The number or composition of CNS intrinsic cells and mononuclear subsets isolated from the CNS were not altered by laquinimod. Conclusion This is the first demonstration that there are no age-associated brain volume changes in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Consequently, laquinimod had no effect on that outcome of this study. Most secondary outcomes on the effects of laquinimod on behavior and the number and composition of CNS-intrinsic cells and mononuclear cells within the CNS were also negative.",
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T1 - Laquinimod has no effects on brain volume or cellular CNS composition in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease

AU - Hussain, Rehana Z.

AU - Miller-Little, William A.

AU - Lambracht-Washington, Doris

AU - Jaramillo, Tom C.

AU - Takahashi, Masaya

AU - Zhang, Shanrong

AU - Fu, Min

AU - Cutter, Gary R.

AU - Hayardeny, Liat

AU - Powell, Craig M.

AU - Rosenberg, Roger N.

AU - Stüve, Olaf

PY - 2017/8/15

Y1 - 2017/8/15

N2 - Background Laquinimod is an anti-inflammatory agent with good central nervous system (CNS) bioavailability, and neuroprotective and myelorestorative properties. A clinical trial in patients with multiple sclerosis demonstrated that laquinimod significantly reduced loss of brain volume. The cellular substrate or molecular events underlying that treatment effect are unknown. In this study, we aimed to explore laquinimod's potential effects on brain volume, animal behavior, cellular numbers and composition of CNS-intrinsic cells and mononuclear cells within the CNS, amyloid beta (Aβ) accumulation and tau phosphorylation in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Methods Utilizing a dose response study design, four months old F1 3xTg-AD/C3H mice were treated for 10 months between ages 4 and 14 months with laquinimod (5, 10, or 25 mg/kg), or PBS administered by oral gavage. Brain volumes were measured in a 7 Tesla magnetic resonance imager (MRI) at ages 4 and 14 months. Behavioral testing included locomotor and rearing activity and the Morris water maze task. Cell numbers and immunophenotypes were assessed by multiparameter flow cytometry. Aβ deposition and tau phosphorylation were determined by immunohistochemistry. Results In the F1 3xTg-AD/C3H animal model of AD, there was no detectable reduction of brain volume over a period of 10 months of treatment, as there was not brain atrophy in any of the placebo or treatment groups. Laquinimod had no detectable effects on most neurobehavioral outcomes. The number or composition of CNS intrinsic cells and mononuclear subsets isolated from the CNS were not altered by laquinimod. Conclusion This is the first demonstration that there are no age-associated brain volume changes in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Consequently, laquinimod had no effect on that outcome of this study. Most secondary outcomes on the effects of laquinimod on behavior and the number and composition of CNS-intrinsic cells and mononuclear cells within the CNS were also negative.

AB - Background Laquinimod is an anti-inflammatory agent with good central nervous system (CNS) bioavailability, and neuroprotective and myelorestorative properties. A clinical trial in patients with multiple sclerosis demonstrated that laquinimod significantly reduced loss of brain volume. The cellular substrate or molecular events underlying that treatment effect are unknown. In this study, we aimed to explore laquinimod's potential effects on brain volume, animal behavior, cellular numbers and composition of CNS-intrinsic cells and mononuclear cells within the CNS, amyloid beta (Aβ) accumulation and tau phosphorylation in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Methods Utilizing a dose response study design, four months old F1 3xTg-AD/C3H mice were treated for 10 months between ages 4 and 14 months with laquinimod (5, 10, or 25 mg/kg), or PBS administered by oral gavage. Brain volumes were measured in a 7 Tesla magnetic resonance imager (MRI) at ages 4 and 14 months. Behavioral testing included locomotor and rearing activity and the Morris water maze task. Cell numbers and immunophenotypes were assessed by multiparameter flow cytometry. Aβ deposition and tau phosphorylation were determined by immunohistochemistry. Results In the F1 3xTg-AD/C3H animal model of AD, there was no detectable reduction of brain volume over a period of 10 months of treatment, as there was not brain atrophy in any of the placebo or treatment groups. Laquinimod had no detectable effects on most neurobehavioral outcomes. The number or composition of CNS intrinsic cells and mononuclear subsets isolated from the CNS were not altered by laquinimod. Conclusion This is the first demonstration that there are no age-associated brain volume changes in the F1 3xTg-AD/C3H mouse model of Alzheimer's disease. Consequently, laquinimod had no effect on that outcome of this study. Most secondary outcomes on the effects of laquinimod on behavior and the number and composition of CNS-intrinsic cells and mononuclear cells within the CNS were also negative.

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