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. 2017;60(4):1429-1442.
doi: 10.3233/JAD-170093.

Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease

Jeyapriya Raja Sundaram  1   2 , Charlene Priscilla Poore  1   3 , Noor Hazim Bin Sulaimee  1   2 , Tej Pareek  4 , Wei Fun Cheong  1   3 , Markus R Wenk  1   3 , Harish C Pant  5 , Sally A Frautschy  6   7 , Chian-Ming Low  1   2   8 , Sashi Kesavapany  1   3
Affiliations

Curcumin Ameliorates Neuroinflammation, Neurodegeneration, and Memory Deficits in p25 Transgenic Mouse Model that Bears Hallmarks of Alzheimer's Disease

Jeyapriya Raja Sundaram et al. J Alzheimers Dis. 2017.

Abstract

Several studies have indicated that neuroinflammation is indeed associated with neurodegenerative disease pathology. However, failures of recent clinical trials of anti-inflammatory agents in neurodegenerative disorders have emphasized the need to better understand the complexity of the neuroinflammatory process in order to unravel its link with neurodegeneration. Deregulation of Cyclin-dependent kinase 5 (Cdk5) activity by production of its hyperactivator p25 is involved in the formation of tau and amyloid pathology reminiscent of Alzheimer's disease (AD). Recent studies show an association between p25/Cdk5 hyperactivation and robust neuroinflammation. In addition, we recently reported the novel link between the p25/Cdk5 hyperactivation-induced inflammatory responses and neurodegenerative changes using a transgenic mouse that overexpresses p25 (p25Tg). In this study, we aimed to understand the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on p25-mediated neuroinflammation and the progression of neurodegeneration in p25Tg mice. The results from this study showed that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice. Moreover, this curcumin-mediated suppression of neuroinflammation reduced the progression of p25-induced tau/amyloid pathology and in turn ameliorated the p25-induced cognitive impairments. It is widely acknowledged that to treat AD, one must target the early-stage of pathological changes to protect neurons from irreversible damage. In line with this, our results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, our data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases.

Keywords: Amyloid; Cdk5; curcumin; neurodegeneration; neuroinflammation; p25; tau.

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Figures

Fig. 1.
Fig. 1.
Expression and activity levels of Cdk5 in curcumin-treated p25Tg mice. A) Confocal images (from the cortex (layer 2/3) (top panels) and hippocampus (CA3 region) (bottom panels) of the brain sections and from 18-week-old wild type mice with normal feed (NFWT), wild type mice with curcumin feed (CFWT), 12-week induced (18-week-old) p25Tg mice with normal feed (NFBT), and p25Tg mice with curcumin feed (CFBT) using anti-GFP antibody (n = 3). Scale bars represent 20 μm. B) Immunoblot analyses results of brain lysates from the samples same as in (A) using anti-GFP antibody (n = 3). C) Western blot analyses results of brain lysates from 12-week induced p25Tg/control mice with/without curcumin treatment using anti-C8 antibodies (n = 3). D) Quantification of C8 immunoblots in C by densitometric scanning (NS p > 0.05). E) Kinase assay results of the brain lysates from the samples same as in A (n = 3) (***p < 0.001, **p < 0.01, and NS p > 0.05) (one-way ANOVA followed by post-hoc Tukey’s test). Error bars indicate ± s.e.m.
Fig. 2.
Fig. 2.
Curcumin reduces p25-induced astrocyte activation in p25Tg mice. A) Representative immunofluorescence images from the cortex (layer 2/3) (top panels) and hippocampus (CA3 region) (bottom panels) of the brain sections from 18-week-old wild type mice with normal feed (NFWT), wild type mice with curcumin feed (CFWT), 12-week induced (18-week old) p25Tg mice with normal feed (NFBT), and p25Tg mice with curcumin feed (CFBT) (n = 3) using anti-GFAP (red) and DAPI (blue). Scale bars represent 20 μm. B) Immunoblot analyses results of brain lysates from the samples same as in (A) using anti-GFAP antibody (n = 3). C) Quantification of GFAP immunoblots in by densitometric scanning (***p < 0.001, one-way ANOVA followed by post-hoc Tukey’s test). D) Western blot analyses results of brain lysates from 18-week-old NFWT, CFWT, 12-week induced (18-week-old) NFBT, and CFBT mice (n = 3) using anti-cPLA2 and anti-tubulin (bottom panel) antibodies. E) Quantification of immunoblots in (A) by densitometric scanning (***p < 0.001, **p < 0.01, *p < 0.05 and NS p > 0.05). F) cPLA2 activity assay results for the mice groups same as in (D) (**p < 0.01, *p < 0.05, and NS p > 0.05). G) Lysophosphatidylcholine (LPC) levels were analyzed using mass spectrometric analyses with lipids extracted from the forebrain samples of the mice groups same as in (A) (n = 3) (***p < 0.001, *p < 0.05, and NS p > 0.05) (one-way ANOVA followed by post-hoc Tukey’s test). Error bars indicate ± s.e.m.
Fig. 3.
Fig. 3.
Reduced pro-inflammatory microglial activation and chemokine/cytokine expression levels in curcumin-treated p25Tg mice. A) Confocal images from the cortex and hippocampus of the brain sections from 18-week-old wild type mice with normal feed (NFWT), wild type mice with curcumin feed (CFWT), 12-week induced (18-week-old) p25Tg mice with normal feed (NFBT), and p25Tg mice with curcumin feed (CFBT) (n = 3) using anti-Cd11b antibody (red). Nuclei were stained with DAPI (blue). Scale bars represent 20 μm. B) Western blot analyses results of brain lysates from 12-week induced p25Tg/control mice with/without curcumin treatment using anti-Cd11b antibody (n = 3). C) Quantification of Cd11b immunoblots in (B) by densitometric scanning (**p < 0.01 and NS p > 0.05) (one-way ANOVA followed by post-hoc Tukey’s test). Real-Time PCR results for (D) MIP-1α, (E) TNF-α, (F) TGF-β, and (G) IL-β expression levels in 12-week induced p25Tg/control mice with/without curcumin treatment (n = 3) (***p < 0.001, **p < 0.01, and NS p > 0.05) (one-way ANOVA followed by post-hoc Tukey’s test). Error bars indicate ± s.e.m.
Fig. 4.
Fig. 4.
Curcumin attenuates p25-mediated tau hyperphosphorylation in p25Tg mice. A) Brain sections from 18-week-old wild type mice with normal feed (NFWT), wild type mice with curcumin feed (CFWT), 12-week induced (18-week-old) p25Tg mice with normal feed (NFBT), and p25Tg mice with curcumin feed (CFBT) (n = 3) were immunostained with phospho-tau antibody AT8 (red). Nuclei were stained with DAPI (blue). Scale bars represent 20 μm. B) Immunoblot analyses results of brain lysates from 12-week induced p25Tg/control mice with/without curcumin treatment using anti-AT8 antibody (n = 3). C) Quantification of immunoblots in (B) by densitometric scanning (**p < 0.01, *p <0.05, and NS p > 0.05) (one-way ANOVA followed by post-hoc Tukey’s test). Error bars indicate ± s.e.m.
Fig. 5.
Fig. 5.
Amyloid accumulation is reduced in curcumin-treated p25Tg mice. A) Representative immunofluorescence images from the cortex (layer 2/3) (top panels) and hippocampus (CA3 region) (bottom panels) of the brain sections from 18-week-old wild type mice with normal feed (NFWT), wild type mice with curcumin feed (CFWT), 12-week induced (18-week-old) p25Tg mice with normal feed (NFBT), and p25Tg mice with curcumin feed (CFBT) (n = 3) using anti-Aβ1-42 antibody (red) and DAPI (blue). Thioflavin-S staining images (B) and Bielschowsky silver staining images (C) from the brain sections of the mice groups same as in (A). Scale bars represent 20 μm.
Fig. 6.
Fig. 6.
Curcumin reduces neuronal apoptosis and ameliorates cognitive deficits in p25Tg mice. A) Brain sections from the cortex (layer 2/3) (top panels) and hippocampus (CA3 region) (bottom panels) of 18-week-old wild type mice with normal feed (NFWT), wild type mice with curcumin feed (CFWT), 12-week induced (18-week-old) p25Tg mice with normal feed (NFBT), and p25Tg mice with curcumin feed (CFBT) (n = 3) were immunostained with anti-cleaved caspase-3 antibody (green) and DAPI (blue). Scale bars represent 20 μm. B, C) Eight-arm radial maze performance was examined for 12-week induced NFBT (n = 5), CFBT (n = 6), NFWT (n = 5), and CFWT (n = 6) mice. B) Bar graph represents the average number of working memory errors (average of 10 sessions) (**p < 0.01) (one-way ANOVA followed by post-hoc Tukey’s test) and (C) line graph represents the average number of reference memory errors (average of sessions per day (10 sessions in 6 days)) (*p < 0.05 compared to NFWT mice, #p < 0.05 compared to CFWT mice and ± p < 0.05 compared to CFBT mice) (repeated measures ANOVA followed by post hoc Tukey’s test). Error bars indicate ± s.e.m.
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