Sulforaphene, a CDK5 Inhibitor, attenuates cognitive deficits in a transgenic mouse model of Alzheimer's disease via reducing Aβ Deposition, tau hyperphosphorylation and synaptic dysfunction.

Abstract

Alzheimer's disease (AD) is the most common form of neurodegenerative disorder characterized by progressive loss of memory and cognitive functions. There are two pathological hallmarks, including accumulation of amyloid plaques composed of β-amyloid peptide (Aβ) and deposits of neurofibrillatory tangles (NFT). Cyclin-dependent kinase 5 (CDK5), a serine/threonine kinase, plays an important role in synaptic plasticity and cognitive behavior. Sulforaphene (SF) has been demonstrated to exert anti-AD activity in AD rat model. In this study, we aimed to evaluate the cognitive deficits improving effects of SF on in TgCRND8 mice and to elucidate the underlying molecular mechanisms. TgCRND8 mice were intragastrically treated with SF (25 and 50mg/kg) for 4months from 3-month-old. The cognitive functions were assessed using Morris Water Maze Test. Cultured primary mouse neurons were pre-treated with SF, followed by co-treatment with Aβ1-42 oligomers. CDK5 inhibitor (roscovitine) was used to determine the involvement of CDK5/p25 pathway in the anti-AD effects of SF in primary neurons. Our results showed that SF treatment significantly ameliorated the cognitive deficits in TgCRND8 mice and protected primary mouse neurons against Aβ1-42 induced neurotoxicity. SF could modulate the expression of Aβ production related markers, and suppress the phosphorylation of tau protein at specific sites in the TgCRND8 mice. In addition, SF enhanced the expressions of synaptic plasticity related markers and CDK5. SF also markedly suppressed the CDK5/p25 activity. SF is a potent CDK5 inhibitor and a potential therapeutic agent for treatment and prevention of AD. Moreover, SF inhibited the overexpression of CDK5 in primary neurons of mouse.