Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by memory impairment and cognitive decline accompanied by a variety of behavioral disorders and neuropsychiatric symptoms [1,2]. The etiology of sporadic AD appears to be multifactorial. Age is one of the major risk factors for AD [3]. With the aging of the global population, the incidence of AD has increased worldwide. The main pathological features of AD were the presence of amyloid-β (Aβ) fiber and neurofibrillary tangles (NFT) in the brain and the loss of synapses and neurons [4,5]. Aβ is generated by the sequential cleavage of amyloid precursor protein (APP) by β-(beta-site APP cleaving enzyme, BACE) and γ-secretase [6,7]. The formation and clearance of Aβ are in a dynamic equilibrium, disruption of which can cause accumulation of Aβ, leading to its aggregation and inducing toxic cascades including synaptic dysfunction, neuronal apoptosis and inflammatory responses, eventually resulting in the decline in cognitive function [3,5,8].

At present, there is a lack of effective treatments for AD. A series of nutraceutical compounds and dietary components have been shown to have beneficial effects on prevention and intervention of AD [9]. N-3 polyunsaturated fatty acids (PUFAs) are essential components of biological membrane that have vital roles in the development of the nervous system and the formation of synapses [10,11,12]. Poor nutritional status of n-3 PUFAs is associated with reduced brain volume, impaired cognition and accelerated progression to dementia, while higher levels of plasma long-chain n-3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are associated with a lower risk of dementia [13,14]. In AD patients, the abundance of n-3 PUFAs is reduced in plasma and brain phospholipids [15,16]. Accordingly, supplementation of n-3 PUFAs has been shown to alleviate the cognitive decline, reducing amyloid burden and inhibiting Aβ-induced cytotoxicity in AD mouse models [17,18,19,20]. Multiple mechanisms are implicated in the neuroprotection of n-3 PUFAs against AD, including promotion of nonamyloidogenic processing of APP, suppression of inflammatory responses and prevention of oxidative stress [17,19,21]. It is found that n-3 PUFAs reduce Aβ production via decreasing the level of APP and reducing the activity of β- and γ-secretase [19,21]. In contrast, the effects of n-3 PUFAs on Aβ clearance are relatively less understood. N-3 PUFAs are reported to decrease the accumulation of Aβ in neuroblastoma cells by enhancing the activity of insulin-degrading enzyme (IDE), the major enzyme for extracellular degradation of Aβ [22]. However, it is unclear whether additional mechanisms are involved in the reduction of Aβ accumulation by n-3 PUFAs.

In this study, the effects of n-3 PUFAs on Aβ-induced toxicity and the underlying mechanisms were studied using a transgenic C. elegans AD model. It was found that n-3 PUFAs, EPA and DHA, inhibited Aβ-induced paralysis and ROS production while reducing the accumulation of Aβ in the AD worms. Further studies revealed that EPA or DHA treatment significantly increased the activity of proteasomes, thus promoting Aβ proteolysis and decreasing Aβ levels in AD worms. Treating worms with peroxisome proliferator activated receptor (PPAR) γ inhibitor GW9662 abolished the inhibitory effects of n-3 PUFAs on Aβ-induced paralysis and ROS elevation, and prevented the elevation of proteasomal activity by EPA or DHA in AD worms, suggesting that PPARγ-mediated signals played vital roles in the protection of n-3 PUFAs against Aβ-induced toxicity.