Article Figures & Data
Figures
- Figure 1 Impaired contextual memory is associated with levels of soluble fibrillary oligomeric Aβ assemblies
Six-month-old mice were trained and tested for contextual (A) and cued (B) fear memory. Brain lysates were analyzed for levels of soAβ (C), soluble Aβ42/40 (D), and insoluble aggregated Aβ42 (E). Using conformation-specific antibodies, levels of soluble prefibrillar (F) or fibrillar (G) oAβ were analyzed from brain lysates. (H) Brain sections were stained for soluble prefibrillar oAβ assemblies (A11) or nuclear oligomeric assemblies (M78); scale bars = 40 µm; ×20 magnification, counterstain is DAPI. Data are representative littermates; histograms represent mean ± SEM; *p < 0.05; **p < 0.01; ***p < 0.001. Aβ = β-amyloid; Agg. = aggregated; AU = arbitrary units; DAPI = 4',6-diamidino-2-phenylindole; nTg = nontransgenic; oAβ = oligomeric β-amyloid; soAβ = soluble oligomeric β-amyloid.
- Figure 2 Subtle differences in intra- and extraneuronal accumulation of Aβ between Dutch and Dutch/PS1ΔE9 mice
Brains were stained to analyze intracellular accumulation of APP/Aβ (4G8) or extracellular accumulation of Aβ (mOC31). Punctate immunoreactivity to 4G8 was typically observed in Dutch APP/PS1ΔE9 mice, whereas Dutch APP mouse brains typically exhibited perinuclear immunoreactivity. Only Dutch APP/PS1ΔE9 mice accumulated insoluble mOC31-immunoreactive extracellular plaques. Micrographs are representative littermates; scale bars = 10 µm; ×20 magnification. Aβ = β-amyloid.
- Figure 3 Only Dutch APP/PS1ΔE9 mice accumulate insoluble p62
Brain lysates were analyzed for levels of soluble (LC3, p62, α-synuclein) and insoluble (p62) autophagic/lysosomal substrates and APP metabolites (A–E). No impairment of autophagic/lysosomal clearance was observed at this age; however, only Dutch/PS1ΔE9 mice accumulated insoluble p62, which we previously reported to occur before autophagic/lysosomal failure in the brains of TgCRND8 mice19. Western blots are representative littermates, histograms represent mean ± SEM; *p < 0.05; 1-way analysis of variance with Bonferroni post hoc analyses. nTg = nontransgenic.
- Figure 4 Prevention of onset of behavioral deficits following 3-month treatment of Baxter IG in Dutch APP E693Q transgenic mice
Five-month-old female Dutch APP E693Q transgenic mice were given weekly subcutaneous injections of either saline (n = 11) or 2 g/kg neat Baxter IG (n = 12), 2 g/kg IG depleted of anti-fibril Aβ antibodies (fibril Aβ-affinity-depleted IG; n = 11), 2 g/kg IG depleted of anti-oligomer Aβ antibodies (oligomer Aβ-affinity-depleted IG; n = 11), or 2 g/kg IG depleted of both anti-oligomer and anti-fibril Aβ antibodies (Aβ-affinity-depleted IG; n = 11) for 3 months. Unlike treatment of saline, fibril Aβ-affinity-depleted IG and Aβ-affinity-depleted IG, treatment of IG prevented onset of behavioral deficits in novel object recognition (A), Y-maze spontaneous alternation (B), and contextual/cued fear conditioning (C) without affecting anxiety-like behavior in the elevated plus maze (C) in Dutch APP E693Q transgenic mice. Treatment of oligomer Aβ-affinity-depleted IG prevented onset of behavioral deficit in novel object recognition (A) in Dutch APP E693Q transgenic mice. *p < 0.05; **p < 0.01; 1-way analysis of variance with Bonferroni post hoc analyses. Data expressed as mean ± SEM. Aβ = β-amyloid; IG = Immune Globulin.
- Figure 5 Reduction of oligomeric Aβ following 3-month treatment of Baxter IG in Dutch APP E693Q transgenic mice
Five-month-old female Dutch APP E693Q transgenic mice were given weekly subcutaneous injections of either saline (n = 11) or 2 g/kg neat Baxter IG (n = 12), 2 g/kg IG depleted of anti-23 fibril Aβ antibodies (fibril Aβ-affinity-depleted IG; n = 11), 2 g/kg IG depleted of anti-oligomer Aβ antibodies (oligomer Aβ-affinity-depleted IG; n = 11), or 2 g/kg IG depleted of both anti-oligomer and anti-fibril Aβ antibodies (Aβ-affinity-depleted IG; n = 11) for 3 months. Aβ40 (A–D), Aβ42 (E–H), or Aβ42/40 ratio (I–L) were unaffected with all treatments. Treatment with IG reduced brain levels of prefibrillar oligomers (M) and oligomers (N) but not fibrillar oligomers (O) in Dutch APP E693Q transgenic mice. Treatment of fibril Aβ-affinity-depleted IG reduced brain levels of oligomers in Dutch APP E693Q transgenic mice (N). (A, E, I) Total Aβ. (B, F, J) TBS fraction. (C, G, H) Triton-X fraction. (D, H, I) Formic acid fraction. (M, N, O) TBS fraction (n = 5/group). *p < 0.0; **p < 0.01; 1-way analysis of variance with Bonferroni post hoc analyses. Data expressed as mean ± SEM. Aβ = β-amyloid; IG = Immune Globulin.
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