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Krstic et al. Journal of Neuroinflammation 2012, 9:151 Page 8 of 23
http://www.jneuroinflammation.com/content/9/1/151
Figure 1 Prenatal immune challenge results in long-term alterations in interleukin (IL)-1β levels, amyloid precursor protein (APP)
processing, and Tau phosphorylation. (A) After prenatal exposure to polyriboinosinic-polyribocytidilic acid (PolyI:C), elevation of the
proinflammatory cytokines IL-1β in plasma and brain and IL-6 in brain was observed. (B,C) Quantification of APP and its proteolytic fragments in
hippocampal lysates of 15 month-old mice. Western blots (WB, left) and ELISA (right) using anti-N- and C-terminal APP, and Aβ 1–40/1–42 specific
antibodies, respectively. WB values represent mean relative optical density normalized to β-actin and expressed in arbitrary units (AU). Lanes
represent different animals, and the inset highlights the size markers. (D) Overview of longitudinal APP-related biochemical changes (percentage
changes relative to saline (NaCl) occurring after prenatal viral-like infection. (E-F) WB, quantification (15 month-old mice), and longitudinal
changes in Tau phosphorylation in mice prenatally exposed to NaCl or PolyI:C, assessed using anti-paired helical filaments (PHFs), anti-pTau T205 ,
and anti-total Tau antibodies. Values represent mean ± SEM, n = 4 to 7 mice per treatment and age. **P < 0.01, *P < 0.05, #P = 0.08 statistics based
on (A, C, E) Mann–Whitney U-test or (D, F) ANOVA/Fisher LSD test.
Based on these findings, we hypothesized that a second
systemic immune challenge in adulthood might exacerbate
the development of Aβ and Tau neuropathology
in non-transgenic mice. To test this, mice prenatally
exposed to PolyI:C (P) and their saline (N) controls were
challenged during aging (between 9 and 15 months) with
a second PolyI:C injection, or treated with saline, yielding
four treatment groups for comparison (NN, NP, PN, PP;
Table 1). Three months after the immune challenge, biochemical
and/or immunohistochemical analyses were performed
to examine the effect of the second exposure on
AD-like neuropathology. Having seen alterations in microglial
morphology/activity in the prenatally challenged cohort,
we first analyzed potential changes in CD68.
Immunohistochemical analysis showed a significant increase
in CD68 IR in double immune-challenged mice