Display Settings:

Items per page

Results: 9

1.
Figure 7

Figure 7. From: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

Characterization of the inflammation-induced Aβ plaques in 3xTg-AD mice. (A-C) Immunofluorescence staining using anti-Aβ1–16 antibody (red) counterstained with Fluoro-Jade (green) and DAPI (blue) revealed, in addition to the dystrophic neurites (arrows), the presence of degenerating neurons in the core of amyloid deposits in immune-challenged transgenic mice. (D-F) Double-immunofluorescence staining using anti-N-APP (red) and anti-activated caspase-6 (green) confirmed the presence of dystrophic neurites within and around the amyloid deposits. (G-I) Transgene-driven human Aβ aggregates (green, anti-Aβ1–40/42) around the APP/soluble (s)APP (red, anti-N-APP) accumulations in PolyI:C-treated 3xTg-AD mice, in striking similarity to the phenotype seen in human patients with AD (J-L). Note the close association but no colocalization between APP ectodomains and C-terminal, Aβ-containing fragments (G-L). Scale bars = 10 μm.

Dimitrije Krstic, et al. J Neuroinflammation. 2012;9:151-151.
2.
Figure 4

Figure 4. From: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

Microglia activation accompanied by prominent astrogliosis in double immune-challenged non-transgenic mice. Immunoperoxidase staining of brain sections from 18-month-old NP (NaCl at gestation day (GD)17, PolyI:C at 15 months) and PP (polyriboinosinic-polyribocytidilic acid (PolyI:C) at GD17, PolyI:C at 15 months) mice. Increase in (A-D) CD68 and (E-H) glial fibrillary acidic protein (GFAP) immunoreactivity (IR) in the PP hippocampus. (D) Note the strong hypertrophy of CD68-positive microglia in PP versus NP subjects, indicative of their activated state. Quantitative analysis of hippocampal (I) anti-CD68 and (J) GFAP IR representing total area and mean size of activated microglia and astrocytes, respectively. Values are given as mean ± SEM, n = 5 per treatment. *P < 0.05; statistical significance based on Mann–Whitney U test. Scale bars: (A,E) = 500 μm; (C) = 20 μm, (G) = 50 μm.

Dimitrije Krstic, et al. J Neuroinflammation. 2012;9:151-151.
3.
Figure 9

Figure 9. From: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

Inflammation-induced amyloid precursor protein (APP) accumulations represent an early neuropathologic feature in the pathogenesis of Alzheimer’s disease (AD). Extracellular APP or soluble (s)APP-containing amyloid plaques in rodents and humans share striking morphological similarities. Tissue sections obtained from (A-B) 15-month-old double immune-challenged (polyriboinosinic-polyribocytidilic acid (PolyI:C) at GD17, PolyI:C at 12 months) wild-type (WT) mice, (C-D) 1-month-old 3xTg-AD mice exposed to PolyI:C at 4 months, and (E-F) an 88-year-old patient with AD. Images were acquired with the same confocal settings in representative areas within the hippocampal formation: layer III-IV in the lateral entorhinal cortex (ECtx, PP), CA1 stratum radiatum (sr, 3xTg-AD mice), and CA1 stratum pyramidale (sp, human subject). Antibody used: anti-N-APP (red) and anti-Aβ1–40/42 (green). (G) Model proposing an AD mutation-independent role of systemic immune challenges, persistent neuroinflammation, and deterioration of innate immunity in the etiology of the age-associated, sporadic form of AD. Scale bars: (A-E) = 10 μm; (F) = 20 μm.

Dimitrije Krstic, et al. J Neuroinflammation. 2012;9:151-151.
4.
Figure 3

Figure 3. From: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

Age-associated impairments in performance in polyriboinosinic-polyribocytidilic acid (PolyI:C) mice in the Y-maze test. (A-B) ANOVA of the % alternation showed a significant main effect for treatment (F1,54 = 90.1, P < 0.001) and age (F1,54 = 39.8, P < 0.001), and a treatment × age interaction (F3,54 = 70.6, P < 0.001), but no effect for sex (F1,54 = 0.0002, P = 0.988). Fisher's LSD post-hoc analysis confirmed the significant impairment in working-memory performance in the 20 month-old PolyI:C-exposed subjects compared with NaCI-treated subjects in (females: P < 0.001, males: P = 0.003). (C-D) ANOVA of the total distance travelled identified a significant main effect for age (F1,54 = 10.0, P = 0.003) and sex (F1,54 = 16.5, P < 0.001), but no main effect for treatment (F1,54 = 0.51, P = 0.480), indicating that the memory impairment was not confounded by differences in locomotor activity. Post-hoc analysis indicated that males travelled significantly shorter distances than did females (P = 0.0003, Fisher's LSD Post-hoc analysis). (E-F) Similarly, ANOVA of the total number of entries into the Y-maze arms showed no significant main effect for treatment (F1,54 = 0.53, P = 0.470), but a main effect for sex (F1,54 = 11.1, P = 0.002), reflecting the lower activity of males relative to females (P = 0.002, Fisher's LSD post-hoc analysis). Besides the effect for age, which closely approached significance (F1,54 = 3.8, P = 0.056), a significant age × sex interaction emerged (F3,54 = 4.2, P = 0.045), indicating the lower activity of old males relative to females. Values are given as mean ± SEM; n = 13 to 18 per age and treatment; ***P < 0.001, **P < 0.01.

Dimitrije Krstic, et al. J Neuroinflammation. 2012;9:151-151.
5.
Figure 6

Figure 6. From: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

Single immune challenge in adults induces a dramatic increase in Aβ plaque burden and prominent neurodegeneration in 3xTg-AD mice. Representative images of (A-B) immunoperoxidase labeling, (C-H) immunofluorescence, and (I-K) silver staining of coronal brain sections of 15-month-old 3xTg-AD mice (Tg) exposed to polyriboinosinic-polyribocytidilic acid (PolyI:C) or NaCI (NaCl) at 4 months of age. (A-B) The typical anti-Aβ1–16 IR seen in the NaCI-treated mice was significantly aggravated after PolyI:C exposure. (C-D) Counterstaining revealed newly formed Aβ plaques in subiculum and CA1 (arrows) that were thioflavinS (ThioS)-negative, suggesting the non-fibrillary nature of the immune challenge-induced plaques. (E-H) Representative images of the ventral CA1 area of (E, F) NaCI-treated and (G,H) PolyI:C-treated transgenic animals, highlighting the striking increase in ThioS-negative Aβ plaques after a single immune challenge. (I-K) The increased plaque deposition in PolyI:C-treated 3xTg-AD mice was accompanied by distinct neurodegeneration. Note the dark precipitates in the vicinity of large plaques in PolyI:C treated mice. (J,K) Higher-magnification color image acquired in the marked area in (J) showing the dense silver precipitates, indicative of dystrophic neurites (red arrows), surrounding Aβ plaques (gray/yellow). Abbreviations: so, stratum oriens; sr, stratum radiatum; slm, stratum lacunosum moleculare; Sub, subiculum; DG, dentate gyrus. (A) = 500 μm; (C) = 150 μm; (E; K) = 50 μm; (I) = 100 μm.

Dimitrije Krstic, et al. J Neuroinflammation. 2012;9:151-151.
6.
Figure 1

Figure 1. From: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

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 Aβ1–40/1–42 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-pTauT205, 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.

Dimitrije Krstic, et al. J Neuroinflammation. 2012;9:151-151.
7.
Figure 2

Figure 2. From: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

Long-term changes induced by a prenatal infection include increased anti- amyloid precursor protein (APP)/Aβ immunoreactivity (IR) and somatodendritic accumulation of pTau IR. Representative images of immunoperoxidase staining using (A,B) anti-Aβ1–40/42 antibody and (D,E,G,H) anti-phosphorylated Tau205 taken from the dorsal hippocampus of 15-month-old non-transgenic mice prenatally exposed to saline (NaCl) or polyriboinosinic-polyribocytidilic acid (PolyI:C). Quantitative analyses of the area covered by (C) anti-APP/Aβ IR or (F) anti-pTau IR in hilar mossy cells. Values are given as mean ± SEM, n = 6 per treatment. *P < 0.05; statistical significance based on Mann–Whitney U test. (D,E) Translocation of pTau IR from axonal to somatodendritic compartments in the dentate gyrus (DG) and hilus after prenatal infection. (G-H) Representative higher-magnification image of the dorsal DG, showing the typical axonal pTau IR in the inner molecular layer of the DG (axonal terminals of contralateral hilar mossy cells, upper arrow) and in the neuropil of the hilus (axonal collaterals of DG granule cells, lower arrow) in NaCI-exposed control subjects. Compared with controls, a pronounced increase in pTau IR in somatic compartments was evident in the PolyI:C-treated offspring, as indicated by the distinct labeling of DG granule cells and hilar mossy cells (red arrows). At the same time, IR in the axonal compartments of the two cell types was strongly reduced. (I) Schematic overview of the observed changes within CA1 and DG between treatment groups, emphasizing the change in subcellular distribution of pTau from axonal to somatodendritic compartments. The drawing on the left highlights the dendritic arborization of a DG granule cell in the outer molecular layer, and indicates the axonal collaterals in the hilus. On the right, the projection of the mossy cells to the inner molecular layer of the DG (commissural; that is, targeting the contralateral hemisphere) are shown. Abbreviations: a, axonal projection area; d, dendritic subfield; gcl, granule cell layer; iml, inner molecular layer; oml, outer molecular layer; s, somatic subfield; slm, stratum lacunosum moleculare. Scale bars: B = 500 μm, H = 50 μm.

Dimitrije Krstic, et al. J Neuroinflammation. 2012;9:151-151.
8.
Figure 5

Figure 5. From: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

An adult immune challenge induces amyloid precursor protein (APP) accumulation in non-transgenic mice prenatally exposed to polyriboinosinic-polyribocytidilic acid (PolyI:C). (A,B) Coronal brain sections of 15-month-old single (NP, NaCl at gestation day (GD)17, PolyI:C at 12 months) and double (PP, PolyI:C at both GD17 and 12 months) immune-challenged mice processed for anti-Aβ1–16 immunoperoxidase staining. Images are color-coded for visual display. (C) Enlarged view (box in B) of a representative precursor plaque. (D) Quantitative analysis of the numerical plaques density in all four treatment groups. Values are given as mean ± SEM, n = 6 to 7 per treatment. *P < 0.05, **P < 0.01; statistical significance based on ANOVA and Fisher LSD post-hoc analysis. (E-F) Confocal images captured in the entorhinal cortex of NP and PP brain sections processed for triple immunofluorescence staining. Activated microglia (CD68, green) were found in close vicinity to the plaques (anti-Aβ1–16) in PP mice. (G) Enlarged neuron in the entorhinal cortex (arrow in F) counterstained with DAPI (blue) displaying intracellular anti-Aβ1–16 IR (red). Bottom image shows confocal view along the xz axis. (H) Anti-N-terminal APP antibody (green) revealed strong accumulation of APP ectodomains in extracellular deposits located in the entorhinal cortex (PP mouse), whereas anti-Aβ1–40/42 (red) IR was seen only in surrounding neurons. (I-K) Pronounced accumulations of APP deposits (anti-Aβ1–16, red) in the cerebral vasculature in PP mice were associated with microglia (anti-CD68 antibody, green). Blue channel shows the DAPI nuclear counterstaining. (L) Western blots of hippocampal lysates obtained from 12-month-old NP and PP mice using anti-N-terminal and anti-C-terminal APP antibodies. (M) Quantitative analysis of the immunoreactive signals. Values represent mean relative optical density normalized to β-Actin and expressed in arbitrary units (AU) (mean ± SEM, n = 6 to 7). ***P < 0.001, **P < 0.01, *P < 0.05, #P = 0.08; statistics is based on Mann–Whitney U test. Scale bars: (B) = 500 μm, (C,F,I) = 20 μm, (G) = 5 μm, (H) = 10 μm.

Dimitrije Krstic, et al. J Neuroinflammation. 2012;9:151-151.
9.
Figure 8

Figure 8. From: Systemic immune challenges trigger and drive Alzheimer-like neuropathology in mice.

Aggravated Tau pathology after systemic infection in adult mice. Representative images of coronal brain sections obtained from (AD) NP (NaCl at gestation day (GD)17, PolyI:C at 12 months) and (BEF) PP mice (PolyI:C at GD17 and at 12 months), processed for (A,B) immunoperoxidase and (DF) immunofluorescence staining using anti-phosphorylated TauT205 antibodies. (AB) Images are color-coded for visual display, with white/yellow indicating highest and blue/purple lowest staining intensity. (C) Quantitative analysis of the optical density (OD) of pTau IR in the hippocampus of all treatment groups. Values represent mean OD values corrected for non-specific background labeling (mean ± SEM), n = 6 to 7. **P < 0.01, *P < 0.05; statistical significance based on ANOVA/Fisher’s LSD post-hoc analysis. (DF) Increase in pTau IR in CA1 is accompanied by mis-sorting into dendrites and intraneuronal aggregation in non-transgenic PP mice. (F) Enlarged view of the CA1 stratum lacunosum moleculare subfield showing the typical somatic pTau aggregation. (G) Biochemical analysis of Tau phosphorylation using anti-paired helical filaments (PHFs), anti-pTauT205, and anti-total Tau antibodies. Lanes represent individual mice. (H) Quantitative analysis of the immunoreactive signals. Values represent mean relative optical density normalized to β-Actin and expressed in arbitrary units (AU) (mean ± SEM, n = 6 to 7). **P < 0.01; Mann–Whitney U test. Please note that the pTauT205antibody was used for (AB) immunohistochemistry (IHC) and (G) immunoblotting (IB) experiments. Because this antibody can crossreact with Ser199 in mouse Tau, an epitope that can be detected with the AT100 (PHF) antibody [], the increase of pTau IR in (AB) is potentially due to an increase in aggregated pTau in sections. (IJ) Anti-pTauT205 IR in the ventral hippocampus of 15-month-old 3xTg-AD mice injected with NaCI or PolyI:C at 4 months. Insets show higher magnifications of the cortical areas (asterisk) with low transgene expression, and indicate formation of distinct neurofibrillary tangle-like structures after a single systemic infection in transgenic AD mice. Scale bars: (A) = 500 μm, (D) = 30 μm, (F) = 5 μm, (I, inset) = 50 μm, (J) = 500 μm.

Dimitrije Krstic, et al. J Neuroinflammation. 2012;9:151-151.

Display Settings:

Items per page

Supplemental Content

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...
Write to the Help Desk