Abstract：
BACKGROUND:Intracellular deposition of tau protein is a hallmark lesion of Alzheimer's disease. Although it is known this event is secondary to excessive tau phosphorylation, the mechanisms involved remain unknown. We previously reported that the enzyme 5-Lipoxygenase (5LO) acts as a modulator of Aβ peptides formation in vivo, and here we investigate its influence on tau protein. METHODS:Tg2576 mice overexpressing neuronal 5LO were generated and its contribution to endogenous tau levels and metabolism investigated. RESULTS:Although no differences were noted in the levels of total tau for both groups, compared with controls, Tg2576 mice overexpressing 5LO had a significant increase in the phosphorylation state of tau at S396 and S396/S404, as recognized by the antibodies PHF-13 and PHF-1, respectively. By contrast, no phosphorylation changes were observed in other tau epitopes. This increase was associated with a significant elevation in cyclin dependent kinase-5 but not other kinases that have been involved in tau phosphorylation. Additionally, mice overexpressing 5LO had biochemical evidence of altered synaptic integrity because they manifested a reduction in PSD-95, synaptophysin and MAP2. CONCLUSIONS:This study demonstrates a new role for 5LO in regulating endogenous tau metabolism in the central nervous system and supports the hypothesis that its pharmacologic inhibition could be beneficial for Alzheimer's disease-related tau neuropathology.
journal_name
Biol Psychiatryjournal_title
Biological psychiatryauthors
Chu J,Li JG,Ceballos-Diaz C,Golde T,Praticò Ddoi
10.1016/j.biopsych.2012.12.012subject
Has Abstractpub_date
2013-09-01 00:00:00pages
321-8issue
5eissn
0006-3223issn
1873-2402pii
S0006-3223(12)01097-9journal_volume
74pub_type
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journal_title：Biological psychiatry
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doi：
更新日期：1984-04-01 00:00:00
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