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

Article type: Research Article

Authors: Sundaram, Jeyapriya Raja^{a; b; 1} | Poore, Charlene Priscilla^{a; c} | Sulaimee, Noor Hazim Bin^{a; b} | Pareek, Tej^e | Cheong, Wei Fun^{a; c} | Wenk, Markus R.^{a; c} | Pant, Harish C.^f | Frautschy, Sally A.^{g; h} | Low, Chian-Ming^{a; b; d} | Kesavapany, Sashi^{a; c; *}

Affiliations: [a] Neurobiology and Ageing Program, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore, Singapore | [b] Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore | [c] Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore | [d] Department of Anaesthesia, Yong Loo Lin School of Medicine, National University of Singapore, Singapore | [e] Department of Pediatrics, Case Western Reserve University, Cleveland, OH, USA | [f] National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA | [g] Department of Neurology, University of California, Los Angeles, CA, USA | [h] Geriatric Research Education and Clinical Center, Veterans Greater Los Angeles Healthcare System, Los Angeles, CA, USA

Correspondence: [*] Correspondence to: Sashi Kesavapany, NTU Institute for Health Technologies, Nanyang Technological University, Research Techno Plaza, XFrontiers Block, #02-07, 50 Nanyang Drive, Singapore 637553. Tel.: +65 65923516; Fax: +65 67943735; E-mail: [email protected].

Note: [1] Current address: Duke-NUS Medical School Singapore,Singapore.

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

DOI: 10.3233/JAD-170093

Journal: Journal of Alzheimer's Disease, vol. 60, no. 4, pp. 1429-1442, 2017