Abstract
Among the different initiating events in Alzheimer’s disease (AD) pathogenesis, oxidative stress and neuroinflammation are some of the most iimportant. In the central nervous system, the 12/15Lipoxygenase (12/15LO) enzyme is the source of potent pro-oxidants and inflammatory lipid mediators. Previous works showed that this pathway is up-regulated in AD brains and that its pharmacological targeting modulates the phenotype of transgenic mouse models of the disease. Here we investigate the effect of brain 12/15LO gene delivery on the AD-like phenotype of a mouse model with plaques, tangles and behavioral deficits, the 3xTg mice. Compared with controls, mice over-expressing 12/15LO manifested an exacerbation of spatial learning and memory impairments, which was associated with significant increase in Aβ formation and deposition, and accumulation of hyper-phosphorylated insoluble tau secondary to a down-regulation of autophagy. In addition, the same mice manifested a worsening of neuroinflammation and synaptic pathology. Taken together our study supports the hypothesis that the 12/15LO enzymatic pathway by impairing neuronal autophagy plays a functional role in exacerbating AD-related neuropathologies and cognitive impairments. It provides further critical preclinical evidence to justify developing and testing new and selective 12/15LO inhibitors for AD treatment.
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Acknowledgements
Domenico Praticò is the Scott Richards North Star Charitable Foundation Chair for Alzheimer’s Research. This study was supported in part by grants from the Scott Richards North Star Charitable Foundation and the Wanda Simone Endowment for Neuroscience (to DP).
Author's contributions
JGL and DP designed the study; JGL and JC performed the experiments; JGL and DP analyzed the data and drafted the manuscript. All authors have discussed the results and seen the final version of the paper before submission.
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Li, JG., Chu, J. & Praticò, D. Downregulation of autophagy by 12/15Lipoxygenase worsens the phenotype of an Alzheimer’s disease mouse model with plaques, tangles, and memory impairments. Mol Psychiatry 26, 604–613 (2021). https://doi.org/10.1038/s41380-018-0268-1
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DOI: https://doi.org/10.1038/s41380-018-0268-1
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