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. 2011 Jun;178(6):2811-22.
doi: 10.1016/j.ajpath.2011.02.012. Epub 2011 Apr 30.

Inflammation Induced by Infection Potentiates Tau Pathological Features in Transgenic Mice

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Free PMC article

Inflammation Induced by Infection Potentiates Tau Pathological Features in Transgenic Mice

Michael Sy et al. Am J Pathol. .
Free PMC article

Abstract

Comorbidities that promote the progression of Alzheimer's disease (AD) remain to be uncovered and evaluated in animal models. Because elderly individuals are vulnerable to viral and bacterial infections, these microbial agents may be considered important comorbidities that could potentiate an already existing and tenuous inflammatory condition in the brain, accelerating cognitive decline, particularly if the cellular and molecular mechanisms can be defined. Researchers have recently demonstrated that triggering inflammation in the brain exacerbates tau pathological characteristics in animal models. Herein, we explore whether inflammation induced via viral infection, compared with inflammation induced via bacterial lipopolysaccharide, modulates AD-like pathological features in the 3xTg-AD mouse model and provide evidence to support the hypothesis that infectious agents may act as a comorbidity for AD. Our study shows that infection-induced acute or chronic inflammation significantly exacerbates tau pathological characteristics, with chronic inflammation leading to impairments in spatial memory. Tau phosphorylation was increased via a glycogen synthase kinase-3β-dependent mechanism, and there was a prominent shift of tau from the detergent-soluble to the detergent-insoluble fraction. During chronic inflammation, we found that inhibiting glycogen synthase kinase-3β activity with lithium reduced tau phosphorylation and the accumulation of insoluble tau and reversed memory impairments. Taken together, infectious agents that trigger central nervous system inflammation may serve as a comorbidity for AD, leading to cognitive impairments by a mechanism that involves exacerbation of tau pathological characteristics.

Figures

Figure 1
Figure 1
A single MHV injection selectively exacerbates tau pathological characteristics in an aged 3xTg-AD mouse. A: Immunoblot analyses of APP processing and tau pathological features 2 or 4 weeks after MHV infection. Densitometric analyses of these bands are shown in Supplemental Figure S3 (available at http://ajp.amjpathol.org). B: Quantitative analysis of soluble and insoluble Aβ in the brain of sham- or MHV-treated 3xTg-AD mice. No significant difference was observed in Aβ levels (n = 5). C: Representative Aβ plaque burden in the hippocampal region of sham- or MHV-treated 3xTg-AD mice (4 weeks after injection). D: Representative immunostaining of tau in the hippocampus. Total tau (HT7) and phospho-tau (phosphorylated at Ser202/Thr205). E: Representative Aβ and tau immunohistological staining on NonTg mice that received a single MHV injection. No obvious Aβ or tau accumulation is detected (n = 5). Scale bars: 100 μm (C); 200 μm (D, left); 30 μm (D, right); 200 μm (E). CTF indicates; GAPDH, glyceraldehyde-3-phosphate dehydrogenase.
Figure 2
Figure 2
Aβ load is not altered in LPS-treated 3xTg-AD mice. A: APP levels by Western blot analysis using 6E10 antibody appear unchanged between LPS- and saline-treated mice. B: Aβ load, as determined by ELISA, is not significantly different between LPS- and saline-treated mice. C: Representative 6E10 immunoreactivity in saline- and LPS-treated mice reveals similar levels of both intraneuronal and extracellular Aβ. Scale bar = 100 μm. D: Plaque counts between saline- and LPS-treated mice are not significantly different.
Figure 3
Figure 3
Phospho-tau is increased in LPS-treated 3xTg-AD mice. A: Mice with chronic inflammation have reduced levels of tau by immunoblot, as evident with antibody HT7. Phospho-tau, as evident with antibody AT100 [Thr212 (T212) or Ser214 (S214)], is increased in LPS-treated mice. B: Quantification of the immunoblots shows that total tau levels, as measured by HT7, are significantly decreased in the soluble fraction, whereas phospho-tau is significantly increased (*P < 0.05, n = 5). C: Representative AT8 immunoreactivity showing increased levels of AT8 reactivity in LPS-treated mice. Scale bar = 100 μm. D: The number of AT8 immunoreactive cells in the subiculum and CA1 hippocampus is significantly increased in LPS-treated mice (*P < 0.05, n = 5).
Figure 4
Figure 4
Insoluble tau and phospho-tau is increased in LPS-treated 3xTg-AD mice. A: Representative HT7 and PHF-1 immunoblot of formic acid fractions shows increased levels of tau and phosphorylated tau in LPS-treated mice. B: Quantification of HT7 and PHF-1 immunoblot shows significantly increased levels of tau and PHF-1–positive tau in the formic acid fraction of LPS-treated mice (*P < 0.05, n = 5). C: Representative PHF-1 reactivity shows increased levels of PHF-1 in LPS-treated mice. PHF-1–immunoreactive neurons in the subiculum and CA1 hippocampus are significantly increased in LPS-treated mice (*P < 0.05, n = 5). Scale bar = 100 μm.
Figure 5
Figure 5
GSK-3β–dependent mechanism underlies the increase in phospho-tau in 3xTg-AD mice with advanced pathological features. A: Representative immunoblots showing decreased levels of GSK-3β phosphorylated at Ser9, p35, and p25 in LPS-treated mice. B: Quantification of immunoblots reveals significantly decreased levels of GSK-3β (S9), p35, and p25 in LPS-treated mice (*P < 0.05, n = 5). a.u. indicates arbitrary unit. C: Kinase assay for GSK-3β activity shows significant increased levels of GSK-3β activity in LPS-treated mice (*P < 0.05, n = 10).
Figure 6
Figure 6
Lithium cotreatment rescues LPS-induced tau pathological characteristics. A: Representative HT7 immunoblots showing increased tau levels in the detergent-soluble fractions of mice treated with both LPS and lithium versus mice treated with only LPS. GSK-3β (S9) is also increased in mice treated with LPS and lithium. B: Quantification of immunoblots shows significantly increased levels of soluble HT7 and GSK-3β (S9) in mice treated with both LPS and lithium. *P < 0.05, n = 6. C: Representative HT7 and PHF-1 immunoblots showing decreased tau levels in the formic acid fractions of mice treated with both LPS and lithium. D: Quantification of immunoblots shows significantly decreased levels of PHF-1–positive tau (*P < 0.05, n = 6).
Figure 7
Figure 7
Aβ and cytokine load is unchanged between LPS-treated mice and mice treated with both LPS and lithium. Detergent-soluble (A) and formic acid–soluble (B) Aβ levels by ELISA are unchanged. C: Levels of IL-1β and IL-6, as measured by ELISA, are unchanged.
Figure 8
Figure 8
Cognitive impairments induced by LPS treatment are prevented by lithium cotreatment in aged 3xTg-AD mice. A: Acquisition curve during the training of MWM. LPS-treated mice require more training to reach criterion. B: LPS-treated mice have a significantly increased latency to cross the platform location in the 1.5-hour probe trial. LPS-treated mice cotreated with lithium perform significantly better than mice treated with LPS only. *P < 0.05 or **P < 0.01 versus the saline-treated group, and ***P < 0.05 versus the LPS-treated group. C: LPS-treated mice are also impaired in the 24-hour probe trial with significantly increased latency to cross the platform and significantly fewer platform crosses versus saline-treated controls. *P < 0.05 versus the saline-treated group, and **P < 0.05 versus the LPS-treated group.

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