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

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.

Protective Effects of Indian Spice Curcumin Against Amyloid-β in Alzheimer’s Disease

“…Sundaram and colleagues (2017) [111] studied the effects of early intervention with a potent natural anti-inflammatory agent, curcumin, on Cdk5 dependent p25-mediated neuroinflammation and the progression of neurodegeneration in p25 transgenic mice. They found that curcumin effectively counteracted the p25-mediated glial activation and pro-inflammatory chemokines/cytokines production in p25Tg mice.…”

“…In line with this, their results demonstrated that early intervention of inflammation could reduce the progression of AD-like pathological outcomes. Moreover, their data provide a rationale for the potential use of curcuminoids in the treatment of inflammation associated neurodegenerative diseases [111]. …”

The impact of curcumin and its modified formulations on Alzheimer's disease

“…Curcumin improved AD-related cognitive deficits via upregulating brain-derived neurotrophic factor (BDNF)-ERK signaling in the hippocampus of rats (L. Zhang et al, 2015). The neuro-inflammation reduced the progression of p25-induced tau/ amyloid pathology and in turn attenuated the p25-induced cognitive deficiency (Sundaram et al, 2017). Curcumin ameliorated AD in transgenic mice by decreasing caveolin-1, inhibiting the abnormal phosphorylation of Tau and inactivating GSK-3β (Sun, Zhang, Wang, Teng, & Li, 2017).…”

The Additive Effects of Low Dose Intake of Ferulic Acid, Phosphatidylserine and Curcumin, Not Alone, Improve Cognitive Function in APPswe/PS1dE9 Transgenic Mice

“…10) Therefore, FA is expected to act relatively upstream of the pathophysiologic mechanism of AD. On the other hand, many studies have reported that Cur not only inhibits Aβ production 28,25) but also inhibits tau phosphorylation 32,39,40) and its aggregation. 41,42) Therefore, Cur is also expected to act downstream of the pathophysiologic mechanism of AD.…”

“…35) Cur also inhibits Aβ aggregation 8,36) and promotes Aβ clearance via up-regulation of degrading enzymes 37) and induction of autophagy. 38) In addition, Cur also reduces hyperphosphorylated tau via down-regulation 39) and inhibition 32) of glycogen synthase kinase 3β (GSK3β) and inhibition of cyclin-dependent kinase 5, 40) inhibits tau aggregation, 41,42) exhibits some kinds of neuroprotective effects, [43][44][45] and promotes neurogenesis via histone acetylase inhibition 46) and BDNF expression. 47) As a result, the incidence of AD in the United States is higher compared to India, where Cur is consumed on a daily basis.…”