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. 2011 Sep;179(3):1095-103.
doi: 10.1016/j.ajpath.2011.05.045. Epub 2011 Jul 19.

MyD88 deficiency ameliorates β-amyloidosis in an animal model of Alzheimer's disease

Jeong-Eun Lim  1 , Jinghong Kou, Min Song, Abhinandan Pattanayak, Jingji Jin, Robert Lalonde, Ken-ichiro Fukuchi
Affiliations

MyD88 deficiency ameliorates β-amyloidosis in an animal model of Alzheimer's disease

Jeong-Eun Lim et al. Am J Pathol. 2011 Sep.

Abstract

The accumulation of β-amyloid protein (Aβ) in the brain is thought to be a primary etiologic event in Alzheimer's disease (AD). Fibrillar Aβ plaques, a hallmark of AD abnormality, are closely associated with activated microglia. Activated microglia have contradictory roles in the pathogenesis of AD, being either neuroprotective (by clearing harmful Aβ and repairing damaged tissues) or neurotoxic (by producing proinflammatory cytokines and reactive oxygen species). Aβ aggregates can activate microglia by interacting with multiple toll-like receptors (TLRs), the pattern-recognition receptors of the innate immune system. Because the adapter protein MyD88 is essential for the downstream signaling of all TLRs, except TLR3, we investigated the effects of MyD88 deficiency (MyD88(-/-)) on Aβ accumulation and microglial activation in an AD mouse model. MyD88 deficiency decreased Aβ load and microglial activation in the brain. The decrease in Aβ load in an MyD88(-/-) AD mouse model was associated with increased and decreased protein expression of apolipoprotein E (apoE) and CX3CR1, respectively, compared with that in an MyD88 wild-type AD mouse model. These results suggest that MyD88 deficiency may reduce Aβ load by enhancing the phagocytic capability of microglia through fractalkine (the ligand of CX3CR1) signaling and by promoting apoE-mediated clearance of Aβ from the brain. These findings also suggest that chronic inflammatory responses induced by Aβ accumulation via the MyD88-dependent signaling pathway exacerbate β-amyloidosis in AD.

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Figures

Figure 1
Figure 1
Detection of diffuse and fibrillar Aβ deposits by anti-Aβ antibody and thioflavin S and quantification of buffer-extractable and buffer-unextractable Aβ by ELISA in APP MyD88−/− and APP mice. Aβ deposits in the brain are visualized by immunohistochemical staining using 6E10 antibody in APP MyD88−/− (A) and APP (C) mice. Percentages of areas showing Aβ immunoreactivity measured by morphometry in the hippocampus and neocortex (E) are shown. Fibrillar Aβ deposits in the brain are visualized by thioflavin S fluorescence in APP MyD88−/− (B) and APP (D) mice. Percentages of areas showing fluorescence measured by morphometry in the hippocampus and neocortex (F) are shown. In the neocortex and hippocampus, the Aβ load in APP MyD88−/− mice is significantly less than that in APP mice. Quantification of buffer-extractable (G) and buffer-unextractable (H) Aβ in the cerebrum of APP MyD88−/− and APP mice at 10 months of age. Levels of buffer-extractable and buffer-unextractable Aβ40 and Aβ42 were determined by ELISA. The data shown are the mean ± SEM of n = 6 for each group (E–H). **P < 0.05, ***P < 0.01, ****P < 0.001. Scale bars = 1 mm.
Figure 2
Figure 2
Steady state levels of APP, C99, BACE1, IDE, NEP, CX3CR1, and apoE in APP MyD88−/− and APP mice. A: Representative immunoblots of APP, C99, BACE1, and GAPDH in buffer-extractable tissue lysates prepared from the cerebrum of APP MyD88−/− and APP mice determined by 6E10 antibody for APP and C99, BASE1 antibody, and GAPDH antibody, respectively. Representative immunoblots of IDE and GAPDH (C), NEP and GAPDH (E), CX3CR1 and GAPDH (G), and apoE and GAPDH (I) in the buffer-extractable tissue lysates. The molecular weights of proteins are indicated on the right in each immunoblot. The bar graphs represent densitometric quantification of each protein indicated after normalization with GAPDH (B, D, F, H, and J). There are no differences in APP, BACE1, C99, IDE, and NEP levels between APP MyD88−/− (n = 6) and APP (n = 6) mice. Decreased CX3CR1 expression and increased apoE expression in the brains of APP MyD88−/− mice (n = 6) are shown compared with in APP mice (n = 6). The data shown are the mean ± SE. **P < 0.003, ***P < 0.01.
Figure 3
Figure 3
Reduced expression of microglial markers and reactive astrocytes in APP MyD88−/− mice. The frozen sections of cerebral cortices from APP MyD88−/− (A–C) and APP (D–F) mice were stained with anti-GFAP (A and D), anti-CD45 (B and E), and anti-CD11b antibody (C and F). Scale bars = 200 μm. G–I: Mean ± SEM percentages of areas showing fluorescence measured by morphometry in the hippocampus and neocortex. The GFAP (G) and CD45 (H) immunoreactivity of the hippocampus and neocortex in APP MyD88−/− mice (n = 6) is less than that in APP mice (n = 6). The hippocampus of APP MyD88−/− mice (n = 6) had significantly less CD11b immunoreactivity than that of APP mice (n = 6) (I), but the difference in CD11b immunoreactivity in the neocortex did not reach statistical significance. *P < 0.03, **P < 0.05.
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