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

Molecular Neurodegeneration

J. Olcese¹  P. C. Bradshaw²  V. Delic²  G. O’Neal-Moffitt¹ 

[1] Department of Biomedical Sciences, College of Medicine, Florida State University Program in Neuroscience, 1115 West Call Street, Tallahassee 32306, FL, USA;Department of Cell Biology, Microbiology, and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, ISA2015, Tampa 33620, FL, USA

关键词: Cytochrome c oxidase;    Mice;    Cognition;    Melatonin receptors;    Alzheimer’s;    Melatonin;   

Others  :  1218644
DOI  :  10.1186/s13024-015-0027-6

 received in 2015-04-17, accepted in 2015-06-30,  发布年份 2015

【 摘 要 】

Background

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.

Results

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 Aβ _1–42levels, 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 16mo 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.

Conclusions

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.

【 授权许可】

   
2015 O'Neal-Moffitt et al.

【 图 表 】

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