Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice - PubMed (original) (raw)

Knockout of 5-lipoxygenase prevents dexamethasone-induced tau pathology in 3xTg mice

Yash B Joshi et al. Aging Cell. 2013 Aug.

Abstract

Emerging evidence suggests that dysregulation stress hormones, such as glucocorticoids, in aged persons put them at a higher risk to develop Alzheimer's disease (AD). However, the mechanisms underlying such vulnerability remain to be unraveled. Pharmacologic inhibition of 5-lipoxygenase (5LO), an active player in AD pathogenesis whose protein level increases with aging in the human, has been shown to blunt glucocorticoid-mediated amyloid β (Ab) formation in vitro. In this article, we investigated the role of this pathway in modulating the development of the corticosteroid-dependent AD-like phenotype in the triple transgenic mice (3xTg). Dexamethasone was administered for 1 week to 3xTg or 3xTg genetically deficient for 5LO (3xTg/5LO-/-) mice, and its effect on memory, amyloid-β and tau levels, and metabolism assessed. At the end of the treatment, we observed that dexamethasone did not induce changes in behavior. Compared with controls, treated mice did not show significant alterations in brain soluble Aβ levels. While total tau protein levels were unmodified in all groups, we found that dexamethasone significantly increased tau phosphorylation at S396, as recognized by the antibody PHF-13, which was specifically associated with an increase in the GSK3β activity. Additionally, dexamethasone-treated mice had a significant increase in the tau insoluble fraction and reduction in the postsynaptic protein PDS-95. By contrast, these modifications were blunted in the 3xTg/5LO-/- mice. Our findings highlight the functional role that 5LO plays in stress-induced AD tau pathology and support the hypothesis that pharmacologic inhibition of this enzyme could be a useful tool for individuals with this risk factor.

Keywords: 5-lipoxygenase; Alzheimer's disease; amyloid; glucocorticoid; tau protein; transgenic mouse models.

© 2013 John Wiley & Sons Ltd and the Anatomical Society.

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Figures

Figure 1

Figure 1

Cognitive deficits are not evident in 3xTg or 3xTg/5LO−/− animals treated with a 7d course of dexamethasone. A) Contextual recall freezing responses in the fear conditioning behavioral paradigm of 3xTg mice treated with PBS/saline (n=5), 3xTg mice treated with dexamethasone 5mg/kg for 7d (n=7), 3xTg/5LO−/− mice (n=4) treated with PBS/saline and 3xTg/5LO−/− mice (n=5) treated with dexamethasone. B) Cued recall in the same animals. C) Spontaneous alternating behavior and D) total entries in the Y-maze.

Figure 2

Figure 2

5LO knockout prevents dexamethasone-induced PHF13 tau phosphorylation. A) Representative western blots for total tau, HT7, PHF13 and PHF1 tau in cortical brain homogenates of 3xTg and 3xTg/5LO−/− animals treated with PBS or dexamethasone. B) Densitometric analysis of PHF13 tau immunoreactivity. C) Representative western blot for insoluble brain HT7. D) Representative immunohistochemical staining for PHF13 and PHF1 tau. *p<0.05

Figure 3

Figure 3

Dexamethasone-mediated increase in the activity of GSK3β is absent in animals that lack 5LO**. A)** Representative western blots for GSK3α, GSK3β, pSer 21 GSK3α, pSer9 GSK3β, cdk5, p35, and p25 in cortical brain homogenates of 3xTg and 3xTg/5LO−/− animals treated with PBS or dexamethasone. B) Densitometric analyses of immunoreactivities to the antibodies shown in panel A. Kinase activity of C) GSK3β and D) cdk5 in brains of animals.

Figure 4

Figure 4

Dexamethasone alters synaptic protein levels in 3xTg animals but not in 3xTg/5LO−/−. A) Representative western blots for PSD95, synaptophysin and glucocorticoid receptor in the cortical brain homogenates of PBS and dexamethasone treated 3xTg and 3xTg/5LO−/− animals. B) Densitometric analysis of PSD95 shown in panel A. *p<0.05

References

    1. Busciglio J, Lorenzo A, Yeh J, Yanker BA. beta-amyloid fibrils induce tau phosphorylation and loss of microtubule binding. Neuron. 1995;14:878–888. - PubMed
    1. Baglietto-Vargas D, Medeiros R, Martinez-Coria H, LaFerla FM, Green KN. Mifepristone alters amyloid precursor protein processing to preclude amyloid beta and tau pathology. Biol Psych. 2013 pii: S0006-3223(12)01097-9. - PMC - PubMed
    1. Chakroborty S, Kim J, Schneider C, Jacobson C, Molgo J, Stuzmann GE. Early presynaptic and postsynaptic calcium signaling abnormalities mask underlying synaptic depression in presymptomatic Alzheimer’s disease mice. J Neurosci. 2012;32:8341–53. - PMC - PubMed
    1. Chu J, Giannopoulos PF, Ceballos-Diaz C, Golde TE, Pratico D. 5-lipoxygenase gene transfer worsens memory, amyloid, and tau brain pathologies in a mouse model of Alzheimer’s disease. Ann Neurol. 2012;72:442–54. - PMC - PubMed
    1. Chu J, Praticò D. 5-lipoygenase as an endogenous modulator of amyloid beta formation in vivo. Ann Neurol. 2011;69:34–46. - PMC - PubMed

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