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. 2017 Apr;23(4):310-320.
doi: 10.1111/cns.12677. Epub 2017 Feb 12.

The role of neuroinflammation and amyloid in cognitive impairment in an APP/PS1 transgenic mouse model of Alzheimer's disease

Affiliations

The role of neuroinflammation and amyloid in cognitive impairment in an APP/PS1 transgenic mouse model of Alzheimer's disease

Shenghua Zhu et al. CNS Neurosci Ther. 2017 Apr.

Abstract

Aims: Both amyloid deposition and neuroinflammation appear in the early course of Alzheimer's disease (AD). However, the progression of neuroinflammation and its relationship with amyloid deposition and behavioral changes have not been fully elucidated. A better understanding the role of neuroinflammation in AD might extend our current knowledge to therapeutic intervention possibilities.

Methods: This study systematically characterized changes in behavioral abnormalities in APP/PS1 transgenic mice. Brain pathology measures were performed in post-mortem brain tissues of mice from 2 to 22 months.

Results: APP/PS1 mice exhibited significant memory deficits from 5 months old, which were aggravated at the later stage of life. However, the degree of memory impairments reached a plateau at 12 months. An early appearance of amyloid plaques was at 3 months with a linear increase throughout the disease course. CD11b-positive microglia and glial fibrillary acidic protein-(GFAP) positive astrocytes were first detected at 3 months with a close association with amyloid plaques. Yet, the rate of changes in glial activation slowed down from 12 months despite the steady increase in Aβ.

Conclusion: These findings provided evidence that neuroinflammation might be involved in the development and progression of cognitive deficits in APP/PS1 mice, suggesting novel intervention and prevention strategies for AD.

Keywords: Alzheimer's disease; astrocyte; microglia; neuroinflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Short‐term working memory in the 3‐, 5‐, 9‐, and 12‐month‐old APP/PS1 and WT mice in a Y‐maze test. (A) Spontaneous alternations of mice in Y‐maze test. (B) Total arm entries of mice in Y‐maze test. Data are expressed as means±SEM n=9‐15 mice per group. *P<.05 vs age‐matched WT mice
Figure 2
Figure 2
Spatial memory in the 3‐, 5‐, 9‐, and 12‐month‐old APP/PS1 and WT mice in a Morris water maze test. (A) Escape latency of mice in the hidden‐platform test of the Morris water maze. (B) Percentage of time spent searching for the target (trained) quadrant in the probe test of the Morris water maze. (C) Number of target area (training platform area) crossing in the probe test. Data are expressed as means±SEM n=8‐13 mice per group. *P<.05 vs age‐matched WT mice
Figure 3
Figure 3
Percentage of cognitive impairment (increase in the mean latency to reach the hidden platform in all trials of all sessions during acquisition in the Morris water maze) of APP/PS1 mice at the age of 3, 5, 9, and 12 months vs age‐matched WT mice which were defined as 100%. Data are expressed as means±SEM n=32‐52 per group. *P<.05 vs age‐matched WT mice
Figure 4
Figure 4
Amyloid deposition with age in APP/PS1 mice. Coronal sections from mice at the age of 2, 3, 5, 9, 12, and 22 months were labeled with an Aβ‐specific monoclonal antibody 4G8 or Congo red or Thioflavin T. (A) Representative illustrations of amyloid plaques stained with 4G8 at the age of 2 (a), 3 (b), 5 (c), 9 (d), 12 (e), and 22 (f) months were shown. Scale bar represents 500 μm. (B) Representative staining of brain sections from 5‐month‐old mice with Congo red and Thioflavin T. Scale bar represents 500 μm. (C) and (D) showed the quantification of amyloid plaques in cerebral cortex and hippocampus after 4G8 immunohistochemistry. Data were representative of three to nine sections from three to six animals. One‐way ANOVA followed by a Newman‐Keuls post hoc test. *P<.05, **P<.01 vs 3‐month‐old group; # P<.05, ## P<.01 vs 5‐month‐old group
Figure 5
Figure 5
Time course of microglial activation in cerebral cortex and hippocampus of APP/PS1 mice. Coronal sections from mice at the age of 2, 3, 5, 9, 12, and 22 months were labeled with an anti‐CD11b antibody. (A) Representative immunohistochemical staining with CD11b at the age of 2 (a), 3 (b), 5 (c), 9 (d), 12 (e), and 22 (f) months were shown. (g‐j) Double‐labeled fluorescent staining of amyloid plaque (4G8; red) and microglia (CD11b; green) in the hippocampus of mice at 12 months of age. Scale bar represents 500 μm in a‐f and 20 μm in g‐j. (B) Quantification of CD11b‐positive areas in cerebral cortex and hippocampus. Data are expressed as means±SEM n=3‐6 animals per group. One‐way ANOVA followed by a Newman‐Keuls post hoc test. *P<.05, **P<.01 vs 3‐month‐old group; # P<.05, ## P<.01 vs 5‐month‐old group
Figure 6
Figure 6
Astrocyte activation in cerebral cortex and hippocampus of APP/PS1 and WT mice. Coronal sections from mice at the age of 2, 3, 5, 9, 12, and 22 months were labeled with an anti‐GFAP antibody. (A) Representative immunohistochemical staining with GFAP at the age of 2 (a, b), 3 (c, d), 5 (e, f), 9 (g, h), 12 (i, j), and 22 (k, l) months was shown. Scale bar represents 200 μm. (B) Quantification of GFAP‐positive areas in cerebral cortex and hippocampus. Data are expressed as means±SEM n=3‐6 animals per group. One‐way ANOVA followed by a Newman‐Keuls post hoc test. *P<.05, **P<.01 vs 3‐month‐old APP/PS1 mice; ## P<.01 vs 5‐month‐old APP/PS1 mice
Figure 7
Figure 7
No neuronal cell loss in cerebral cortex and hippocampus of APP/PS1 compared age‐matched WT mice. Coronal sections from mice at the age of 2, 3, 5, 9, 12, and 22 months were labeled with a neuronal marker NeuN. Representative immunohistochemical staining with NeuN at the age of 2 (a, b), 3 (c, d), 5 (e, f), 9 (g, h), 12 (i, j), and 22 (k, l) months was shown. Scale bar represents 200 μm. No statistical significance was detected in total number of NeuN‐positive cells in cerebral cortex and hippocampus

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