Neurodegenerative diseases such as Alzheimer's disease (AD) and the polyglutamine (polyQ) diseases are considered to share a common molecular pathogenesis which involves protein misfolding and aggregation. Recent epidemiological and experimental studies have revealed that diabetes mellitus and high caloric diet increase the risk for development of AD. However, the molecular mechanisms as to how dietary condition affects misfolding-related neurodegeneration are not fully understood. To address this issue, we employed Drosophila models, which are widely used to study neurodegenerative diseases and are suitable for genetic analysis. We fed AD and the polyQ diseases model flies a high-nutrient diet (HND) or a low-nutrient diet (LND), and found that HND significantly enhances compound eye degeneration, locomotor dysfunction and shortened life-span of these flies. HND also accelerated aggregation of the polyQ protein without affecting the protein expression level. However, HND did not affect the compound eye degeneration induced by Grim, an apoptosis-inducing molecule, suggesting that its effects are specific to protein aggregation-related neurodegeneration. Moreover, the microarray and genetic analyses showed that the insulin/IGF-like signaling pathways and the innate immune signaling pathways mediate the HND-induced aggravation. Our findings demonstrate that the high-nutrient condition aggravates neurodegeneration through affecting protein misfolding, and suggest the role of metabolic and immune signaling in the effect of the dietary condition.