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Prophylactic melatonin significantly reduces Alzheimer's neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPP(swe)/PS1 mice.

Title: Prophylactic melatonin significantly reduces Alzheimer's neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPP(swe)/PS1 mice.
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Name(s): O'Neal-Moffitt, G, author
Delic, V, author
Bradshaw, P C, author
Olcese, J, author
Type of Resource: text
Genre: Journal Article
Text
Date Issued: 2015-07-11
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Alzheimer's disease (AD) underlies dementia for millions of people worldwide, and its occurrence is set to double in the next 20 years. Currently, approved drugs for treating AD only marginally ameliorate cognitive deficits, and provide limited symptomatic relief, while newer substances under therapeutic development are potentially years away from benefiting patients. Melatonin (MEL) for insomnia has been proven safe with >15 years of over-the-counter access in the US. MEL exerts multiple complementary mechanisms of action against AD in animal models; thus it may be an excellent disease-modifying therapeutic. While presumed to provide neuroprotection via activation of known G-protein-coupled melatonin receptors (MTNRs), some data indicate MEL acts intracellularly to protect mitochondria and neurons by scavenging reactive oxygen species and reducing free radical formation. We examined whether genetic deletion of MTNRs abolishes MEL's neuroprotective actions in the AβPP(swe)/PSEN1dE9 mouse model of AD (2xAD). Beginning at 4 months of age, both AD and control mice either with or without both MTNRs were administered either MEL or vehicle in drinking water for 12 months. Behavioral and cognitive assessments of 15-month-old AD mice revealed receptor-dependent effects of MEL on spatial learning and memory (Barnes maze, Morris Water Maze), but receptor-independent neuroprotective actions of MEL on non-spatial cognitive performance (Novel Object Recognition Test). Similarly, amyloid plaque loads in hippocampus and frontal cortex, as well as plasma Aβ1-42 levels, were significantly reduced by MEL in a receptor-independent manner, in contrast to MEL's efficacy in reducing cortical antioxidant gene expression (Catalase, SOD1, Glutathione Peroxidase-1, Nrf2) only when receptors were present. Increased cytochrome c oxidase activity was seen in 16 mo AD mice as compared to non-AD control mice. This increase was completely prevented by MEL treatment of 2xAD/MTNR+ mice, but only partially prevented in 2xAD/MTNR- mice, consistent with mixed receptor-dependent and independent effects of MEL on this measure of mitochondrial function. These findings demonstrate that prophylactic MEL significantly reduces AD neuropathology and associated cognitive deficits in a manner that is independent of antioxidant pathways. Future identification of direct molecular targets for MEL action in the brain should open new vistas for development of better AD therapeutics.
Identifier: FSU_pmch_26159703 (IID), 10.1186/s13024-015-0027-6 (DOI), PMC4702331 (PMCID), 26159703 (RID), 26159703 (EID), 10.1186/s13024-015-0027-6 (PII)
Publication Note: This NIH-funded author manuscript originally appeared in PubMed Central at https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702331.
Subject(s): Alzheimer Disease/drug therapy
Alzheimer Disease/genetics
Alzheimer Disease/pathology
Alzheimer Disease/psychology
Amyloid beta-Peptides/blood
Amyloid beta-Protein Precursor/genetics
Animals
Anxiety/genetics
Disease Models, Animal
Drug Evaluation, Preclinical
Exploratory Behavior
Frontal Lobe/metabolism
Frontal Lobe/pathology
Glutathione Peroxidase/biosynthesis
Glutathione Peroxidase/genetics
Hippocampus/metabolism
Hippocampus/pathology
Maze Learning
Melatonin/therapeutic use
Memory Disorders/genetics
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Knockout
Mitochondria/drug effects
Mitochondria/physiology
Mutation
NF-E2-Related Factor 2/biosynthesis
NF-E2-Related Factor 2/genetics
Nerve Tissue Proteins/biosynthesis
Nerve Tissue Proteins/genetics
Neuroprotective Agents/therapeutic use
Peptide Fragments/blood
Plaque, Amyloid/pathology
Presenilin-1/genetics
Receptors, Melatonin/deficiency
Receptors, Melatonin/genetics
Receptors, Melatonin/physiology
Superoxide Dismutase/biosynthesis
Superoxide Dismutase/genetics
Superoxide Dismutase-1
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_pmch_26159703
Owner Institution: FSU
Is Part Of: Molecular neurodegeneration.
1750-1326
Issue: vol. 10

Choose the citation style.
O'Neal-Moffitt, G., Delic, V., Bradshaw, P. C., & Olcese, J. (2015). Prophylactic melatonin significantly reduces Alzheimer's neuropathology and associated cognitive deficits independent of antioxidant pathways in AβPP(swe)/PS1 mice. Molecular Neurodegeneration. Retrieved from http://purl.flvc.org/fsu/fd/FSU_pmch_26159703