Pharmacologic Inhibition of 5-Lipoxygenase Improves Memory, Rescues Synaptic Dysfunction, and Ameliorates Tau Pathology in a Transgenic Model of Tauopathy

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• 作者：Phillip F. Giannopoulos^a ; ^c ; Jin Chu^a ; ^c ; Margaret Sperow^b ; Jian-Guo Li^a ; ^c ; W. Haung Yu^e ; Lynn G. Kirby^b ; ^d ; Mary Abood^b ; ^d ; Domenico Praticò ; ^a ; ^c ; ^{praticod@temple.edu" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Behavior ; 5-Lipoxygenase ; Frontotemporal dementia ; Synapse ; Tau protein ; Tauopathy ; Transgenic tau mice
• 刊名：Biological Psychiatry
• 出版年：2015
• 出版时间：15 November 2015
• 年：2015
• 卷：78
• 期：10
• 页码：693-701
• 全文大小：4803 K

文摘

5-Lipoxygenase (5-LO) is a protein widely distributed in the central nervous system where it modulates amyloidosis and memory impairments in transgenic mouse models of Alzheimer’s disease. However, no data are available as to whether 5-LO is elevated in human tauopathy or if it directly influences tau pathology in a relevant model of the disease.

Methods

We assayed 5-LO levels in brain samples from patients with tauopathy and transgenic tau mice, and we evaluated the effect of 5-LO pharmacologic inhibition on the phenotype of these mice.

Results

The 5-LO protein is upregulated in human tauopathy and transgenic tau mice brains. Pharmacologic blockade of 5-LO in tau mice resulted in significant memory improvement, rescue of synaptic integrity and dysfunction, and reduction of tau pathology via a cdk5-dependent mechanism.

Conclusions

These results establish a key role of 5-LO in the development of the tau pathology phenotype and demonstrate it to be a novel viable therapeutic target for the pharmacologic treatment of human tauopathy.